Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

The goal of treatment of chronic hepatitis C is to achieve a sustained virological response, which is defined as exhibiting undetectable hepatitis C virus (HCV) RNA levels in serum following therapy for at least six months. However, the current treatment is only effective in 50% of patients infected with HCV genotype 1, the most prevalent genotype in Brazil. Inhibitors of the serine protease non-structural protein 3 (NS3) have therefore been developed to improve the responses of HCV-infected patients. However, the emergence of drug-resistant variants has been the major obstacle to therapeutic success. The goal of this study was to evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV from 37 patients infected with HCV genotype 1 had not been treated with protease inhibitors. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene. The results indicate that the catalytic triad is conserved. A large number of substitutions were observed in codons 153, 40 and 91; the resistant variants T54A, T54S, V55A, R155K and A156T were also detected. This study shows that resistance mutations and genetic polymorphisms are present in the NS3 region of HCV in patients who have not been treated with protease inhibitors, data that are important in determining the efficiency of this new class of drugs in Brazil.

Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

The hepatitis C virus (HCV) NS3 protease has been one of the molecular targets of new therapeutic approaches. Its genomic sequence variability in Brazilian HCV isolates is poorly documented. To obtain more information on the magnitude of its genetic diversity, 114 Brazilian HCV samples were sequenced and analysed together with global reference sequences. Genetic distance (d) analyses revealed that subtype 1b had a higher degree of heterogeneity (d = 0.098) than subtypes 1a (d = 0.060) and 3a (d = 0.062). Brazilian isolates of subtype 1b were distributed in the phylogenetic tree among sequences from other countries, whereas most subtype 1a and 3a sequences clustered into a single branch. Additional characterisation of subtype 1a in clades 1 and 2 revealed that all but two Brazilian subtype 1a sequences formed a distinct and strongly supported (approximate likelihood-ratio test = 93) group of sequences inside clade 1. Moreover, this subcluster inside clade 1 presented an unusual phenotypic characteristic in relation to the presence of resistance mutations for macrocyclic inhibitors. In particular, the mutation Q80K was found in the majority of clade 1 sequences, but not in the Brazilian isolates. These data demonstrate that Brazilian HCV subtypes display a distinct pattern of genetic diversity and reinforce the importance of sequence information in future therapeutic approaches.

Detecção e quantificação do VHC-RNA no soro e na saliva de pacientes infectados pelo vírus da hepatite C (VHC) / Detection and quantification of HCV-RNA in serum and saliva of patients infected with the hepatitis C virus (HCV)

A infecção causada pelo vírus da hepatite C (VHC) é um importante problema de saúde pública, sendo estimado que 170 milhões de pessoas estejam infectadas no mundo. O VHC pode ser encontrado no sangue e em outros fluidos corpóreos como na saliva, sêmen e suco gástrico o que pode explicar o fato de alguns pacientes possuírem rota de transmissão desconhecida. A utilização de testes qualitativos e quantitativos é imprescindível para diagnosticar a infecção pelo VHC e monitorar a terapia. O presente estudo tem o objetivo de verificar a existência de correlação entre os níveis de carga viral do VHC-RNA na saliva e no soro de pacientes infectados pelo VHC. O nível médio do VHC-RNA encontrado na saliva foi de 2,8x 104 cópias/mL (3,44 lOglO) e 7,44 x 103 cópias/mL (3,60 loglO), enquanto no soro foi de 5,9x 106 cópias/mL (5,87 loglO) e 1,51 x 105 cópias/mL (5,17 loglO) através do PCR em tempo real e Amplicor@, respectivamente. Foi observado que o nível médio do VHC-RNA presente na saliva foi 1,70 loglO e 1,60 loglO vezes inferior ao encontrado no soro, através do PCR em tempo real e Amplicor@, respectivamente. Foi observada diferença estatisticamente significante entre os níveis VHC-RNA no soro e na saliva. No entanto, não foi observada correlação significante entre os níveis VHC-RNA presentes no soro e na saliva. Foi possível quantificar o VHC-RNA nas amostras de soro e saliva dos pacientes. Entretanto não houve correlação entre os níveis de VHC-RNA encontrados na saliva e no soro dos pacientes, sugerindo a necessidade de estudos epidemiológicos para melhor entendimento da importância da saliva como via de transmissão para o VHC.

Biochemical properties of full-length hepatitis C virus RNA-dependent RNA polymerase expressed in insect cells

The hepatitis C virus (HCV) RNA-dependent RNA polymerase, NS5B protein, is the key viral enzyme responsible for replication of the HCV viral RNA genome. Although several full-length and truncated forms of the HCV NS5B proteins have been expressed previously in insect cells, contamination of host terminal transferase (TNTase) has hampered analysis of the RNA synthesis initiation mechanism using natural HCV RNA templates. We have expressed the HCV NS5B protein in insect cells using a recombinant baculovirus and purified it to near homogeneity without contaminated TNTase. The highly purified recombinant HCV NS5B was capable of copying 9.6-kb full-length HCV RNA template, and mini-HCV RNA carrying both 5'- and 3'-untranslated regions (UTRs) of the HCV genome. In the absence of a primer, and other cellular and viral factors, the NS5B could elongate over HCV RNA templates, but the synthesized products were primarily in the double stranded form, indicating that no cyclic replication occurred with NS5B alone. RNA synthesis using RNA templates representing the 3'-end region of HCV minus-strand RNA and the X-RNA at the 3'-end of HCV RNA genome was also initiated de novo. No formation of dimersize self-primed RNA products resulting from extension of the 3'-end hydroxyl group was observed. Despite the internal de novo initiation from the X-RNA, the NS5B could not initiate RNA synthesis from the internal region of oligouridylic acid (U)20, suggesting that HCV RNA polymerase initiates RNA synthesis from the selected region in the 3'-UTR of HCV genome.

Doadores de sangue anti-VHC reagentes: o que significa e qual a conduta a ser adotada / Anti-HCV positive blood donors: what's the meaning and what's the conduct to take

A introducao dos testes por tecnica imunoenzimatica (ELISA) para a deteccao do anti-VHC em doadores de sangue representou um consideravel avanco na profilaxia das hepatites pos-transfusionais. No entanto, com razoavel frequencia, doadores anti-VHC reagentes e com transaminases normais nao sao portadores do VHC, enquanto que aqueles com transaminases elevadas o sao. Os ELISAs atualmente ja estao em sua terceira geracao, existindo variacoes em sua sensibilidade e especificidade. Recomenda-se que doadores anti-VHC reagentes (ELISA) sejam avaliados com testes mais especificos, como, por exemplo, o RIBA. A frequencia com que um doador anti-VHC reagente (ELISA) tem sua infeccao confirmada pelo RIBA e muito variavel. O metodo mais sensivel para identificar viremia e a reacao em cadeia da polimerase. Ha evidencias de que a grande maioria dos doadores anti-VHC reagentes (ELISA e RIBA) sao portadores de hepatopatia, de grau variavel