RESUMO
The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.
Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Resposta Viral Sustentada , Adulto , Idoso , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Antivirais/administração & dosagem , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Ciclopropanos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Cirrose Hepática/virologia , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , RNA Viral/sangue , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Sofosbuvir/administração & dosagem , Sofosbuvir/uso terapêutico , Sulfonamidas , Resultado do Tratamento , ValinaRESUMO
Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks are approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 8 weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12 months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotypes 1a and 1, no subtype) for 8 weeks. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Thirty people (median age 38 years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n = 23) were HIV-positive, 93% (n = 28) had genotype 1a infection and 53% (n = 16) had ever injected drugs. Median maximum ALT in the preceding 12 months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT > 10 x ULN was documented in 83% (n = 25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51), and median HCV RNA was 5.7 log10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n = 1; per protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks were highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. These data support the use of this shortened duration direct-acting antiviral regimen in this population.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C/tratamento farmacológico , 2-Naftilamina , Adulto , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , Austrália/epidemiologia , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/farmacologia , Ciclopropanos , Esquema de Medicação , Quimioterapia Combinada , Inglaterra/epidemiologia , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Análise de Intenção de Tratamento , Lactamas Macrocíclicas , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/efeitos adversos , Compostos Macrocíclicos/farmacologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Prolina/análogos & derivados , Estudos Prospectivos , RNA Viral/sangue , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ribavirina/farmacologia , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacologia , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/análogos & derivados , Uracila/farmacologia , ValinaRESUMO
Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.
Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Amidas , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , Carbamatos , Ciclopropanos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , RNA Viral , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sulfonamidas , Fatores de Tempo , Falha de Tratamento , Resultado do Tratamento , Carga ViralRESUMO
A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , DNA Viral/genética , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Humanos , Mutação , Organofosfonatos/uso terapêutico , Análise de Sequência de DNARESUMO
One challenge to HCV elimination through therapeutic intervention is reinfection. The aim of this analysis was to calculate the incidence of HCV reinfection among both HIV-positive and HIV-negative individuals treated for recent HCV infection (estimated infection duration <18 months). Individuals with recent HCV infection who achieved an end-of-treatment response in four open-label studies between 2004 and 2015 in Australia and New Zealand were assessed for HCV reinfection, confirmed by sequencing of the Core-E2 and/or NS5B regions. Reinfection incidence was calculated using person-time of observation. Exact Poisson regression analysis was used to assess factors associated with HCV reinfection. The cohort at risk for reinfection (n=120; 83% male; median age 36 years) was composed of HIV-positive men-who-have-sex-with-men (53%) and people who inject drugs (current 49%, ever 69%). Total follow-up time at risk was 135 person-years (median 1.08 years, range 0.17, 2.53). Ten cases of HCV reinfection were identified, for an incidence of 7.4 per 100 py (95% CI 4.0, 13.8). Reinfection incidence was significantly higher among participants who reported injection drug use at end of or post-treatment, irrespective of HIV status (15.5 per 100 py, 95% CI 7.8, 31.1). In adjusted analysis, factors associated with reinfection were older age (aIRR 5.3, 95% CI 1.15, 51.5, P=.042) and injection drug use at end of or post-treatment (aIRR 7.9, 95% CI 1.6, 77.2, P=.008). High reinfection incidence following treatment for recent HCV infection in individuals with ongoing risk behaviour emphasizes the need for post-treatment surveillance, harm reduction strategies and education in at-risk populations.
Assuntos
Antirretrovirais/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Adulto , Austrália/epidemiologia , Feminino , Seguimentos , Genótipo , Técnicas de Genotipagem , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Filogenia , Recidiva , Fatores de Risco , Assunção de Riscos , Análise de Sequência de DNA , Proteínas Virais/genéticaRESUMO
Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow-up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long-term follow-up. (EudraCT 2012-002457-29).
Assuntos
Hepacivirus , Veias Hepáticas/fisiopatologia , Hepatite C/complicações , Hepatite C/virologia , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Pressão na Veia Porta , Adulto , Idoso , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Resposta Viral Sustentada , Fatores de Tempo , Carga ViralRESUMO
High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA Assuntos
Antivirais/administração & dosagem
, Genótipo
, Hepacivirus/classificação
, Hepatite C Crônica/tratamento farmacológico
, Hepatite C Crônica/virologia
, Resposta Viral Sustentada
, Adolescente
, Adulto
, Idoso
, Anilidas
, Carbamatos
, Ensaios Clínicos Fase III como Assunto
, Feminino
, Hepacivirus/genética
, Hepacivirus/isolamento & purificação
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Prolina
, RNA Viral/sangue
, Fatores de Tempo
, Resultado do Tratamento
, Valina
, Adulto Jovem
RESUMO
Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.
Assuntos
Genótipo , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/classificação , Hepatite B Crônica/tratamento farmacológico , Imunidade Inata , Receptores de Interleucina-1/metabolismo , Receptor 2 Toll-Like/metabolismo , Adulto , Antivirais/uso terapêutico , Células Cultivadas , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatócitos/imunologia , Humanos , Interferon-alfa/uso terapêutico , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).
Assuntos
Antivirais/uso terapêutico , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Amidas , Antivirais/efeitos adversos , Carbamatos , Ciclopropanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Recidiva , Ribavirina/efeitos adversos , Sulfonamidas , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
AIM: People with inherited bleeding disorders have been disproportionally affected by HCV. We assessed the fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) with the NS5B polymerase inhibitor sofosbuvir (SOF) with ribavirin (RBV) in patients with genotype 1 HCV and inherited bleeding disorders. METHODS: To be eligible, patients had to be over 18 years of age and have an inherited bleeding disorder. HCV treatment-naïve and -experienced patients could enrol. All patients received LDV 90 mg per SOF 400 mg once daily and weight-based RBV in a divided dose for 12 weeks. The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA below the limit of detection (15 IU mL-1 ) 12 weeks after the end of treatment (SVR12). RESULTS: Of the 14 patients enrolled, 8 (57%) had haemophilia A, 3 (21%) had haemophilia B and 2 (14%) had von Willebrand disease, and 1 (7%) had factor XIII deficiency. All 14 patients (100%, 95% CI: 77-100%) achieved SVR12. Treatment was well tolerated: all patients completed therapy, with mostly mild adverse events. No specific safety concerns associated with the patient's underlying bleeding disorders were noted. CONCLUSION: These results appear to suggest that people with HCV and inherited bleeding disorders can be safely and effectively treated with 12 weeks of LDV/SOF plus RBV.
RESUMO
Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.
Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Mutação de Sentido Incorreto , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/genética , Evolução Molecular , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estudos Longitudinais , Filogenia , RNA Viral/genética , RecidivaRESUMO
Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.
Assuntos
Hepatite C Crônica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Criança , Pré-Escolar , Uso de Medicamentos/estatística & dados numéricos , Feminino , Saúde Global , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/cirurgia , Humanos , Lactente , Recém-Nascido , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.
Assuntos
Antivirais/uso terapêutico , Efeitos Psicossociais da Doença , Hepatite C Crônica/tratamento farmacológico , Programas de Rastreamento , Modelos Biológicos , Progressão da Doença , Saúde Global , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/epidemiologia , Humanos , Prevalência , Resultado do TratamentoRESUMO
Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.
Assuntos
Antivirais/uso terapêutico , Efeitos Psicossociais da Doença , Hepatite C Crônica/epidemiologia , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Progressão da Doença , Feminino , Saúde Global , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
Poor outcomes are reported in young people with chronic health conditions. We performed a retrospective notes review of New Zealand paediatric liver transplant recipients transferred to adult services. Two patients were lost to follow up. Out of 20, 12 were non-adherent, and out of 12, 7 developed rejection. Other risk behaviours were common in the non-adherent group. We conclude that dedicated services for these young people may be needed to optimise outcomes.
Assuntos
Transplante de Fígado , Adesão à Medicação/estatística & dados numéricos , Autocuidado/psicologia , Transição para Assistência do Adulto/organização & administração , Transplantados/estatística & dados numéricos , Adolescente , Criança , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Adesão à Medicação/psicologia , Nova Zelândia/epidemiologia , Cooperação do Paciente , Pediatria , Estudos Retrospectivos , Transplantados/psicologia , Adulto JovemRESUMO
BACKGROUND: Liver cirrhosis is an important cause of morbidity and mortality; however, little is known about its impact in New Zealand. AIMS: We aim to determine the disease burden, epidemiology and outcomes of cirrhotic patients. METHODS: This is a retrospective study of cirrhosis patients under secondary public hospital care in a geographically defined region, between the years 2000 and 2011. Cirrhosis complications and mortality was recorded. Poisson log-linear regression analysis was performed for incidence rate ratio (IRR) and Cox regression analysis was used to analyse time-related events. RESULTS: Seven hundred and forty-six cirrhotic patients were analysed; most were European/Other (39.9%), Pacific islanders (21.6%), Southeast Asian/Chinese (17.8%) and Maori (12.3%). 68.4% were male. The common primary aetiologies for cirrhosis were chronic hepatitis B (CHB) cirrhosis (37.3%), alcoholic liver disease (ALD) cirrhosis (24.1%), chronic hepatitis C (CHC) cirrhosis (22.3%) and non-alcoholic fatty liver disease (NAFLD) cirrhosis (16.4%). The hepatocellular carcinoma (HCC) mortality rates were highest in NAFLD and CHB cirrhosis groups (3.0 and 3.1 per 100 patient-year respectively), compared with ALD and CHC groups (2.2 and 1.4 per 100 patient-year, all P < 0.05 respectively). Patients with ALD and NAFLD cirrhosis had the highest all-cause and non-HCC mortality rate compared with viral hepatitis cirrhosis groups. The IRR for HCC incidence, liver-related mortality and HCC mortality were 1.087, 1.098 and 1.114, respectively (all P < 0.001), suggesting increasing incidence and disease burden over the study period. CONCLUSION: The number of cirrhotic patients in secondary care is increasing steadily. Cirrhosis complications and mortality rates are also rising, particularly the incidence and mortality of HCC.
Assuntos
Efeitos Psicossociais da Doença , Cirrose Hepática/economia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Hospitais Públicos , Humanos , Incidência , Modelos Lineares , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Distribuição de Poisson , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Atenção Secundária à Saúde/métodos , Índice de Gravidade de Doença , Análise de Sobrevida , População UrbanaRESUMO
Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug-drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune (Shakespeare: J Caesar Act 4, scene 3).
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Hepatopatias/complicações , Transplante de Fígado/efeitos adversos , Hepatite C Crônica/etiologia , Humanos , Hepatopatias/cirurgia , Hepatopatias/virologia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.
Assuntos
Antivirais/administração & dosagem , Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Timidina/análogos & derivados , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Telbivudina , Timidina/administração & dosagem , Timidina/efeitos adversos , Resultado do TratamentoRESUMO
Recurrent hepatitis C virus (HCV) infection of the allograft occurs universally following liver transplantation. Longitudinal natural history studies have identified several pre- and posttransplant factors associated with more rapid fibrosis progression, including baseline host and viral factors, donor factors and posttransplant immunosuppression effects, such as metabolic syndrome. Evidence accumulated over the past two decades indicates that HCV has metabolic associations, in particular insulin resistance and diabetes mellitus. Approximately half of HCV-positive liver transplant recipients develop posttransplant diabetes mellitus (PTDM), which is associated with accelerated fibrosis progression and poorer graft and patient survival outcomes. This review summarizes the risks and consequences of insulin resistance and PTDM in HCV-positive liver transplant recipients. Risk for developing PTDM is one factor that should be considered when choosing the primary immunosuppressive regimen following liver transplantation. Comparative studies suggest that cyclosporine A-based immunosuppression may provide improved responses to antiviral therapy and reduced incidence of PTDM compared with tacrolimus-based immunosuppression. Addressing insulin resistance and PTDM in HCV-positive liver transplant recipients may have the potential to slow HCV complications and improve survival outcomes.
Assuntos
Complicações do Diabetes/etiologia , Diabetes Mellitus/etiologia , Hepacivirus/patogenicidade , Hepatite C/complicações , Transplante de Fígado/efeitos adversos , Hepatite C/terapia , Humanos , Fatores de RiscoRESUMO
A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.