Antivirais no Tratamento da Hepatite C

Descrição Geral

Vírus da hepatite C (VHC)

• Vírus de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure de cadeira simples
• Família: Flaviviridae Flaviviridae A family of RNA viruses, many of which cause disease in humans and domestic animals. There are three genera flavivirus; pestivirus; and hepacivirus, as well as several unassigned species. Hepatitis C Virus
• Transmissão:
  • Parentérica
    • Sangue e derivados
    • Utilização de fármacos intravenosos
  • Perinatal
  • Relação sexual
• A infeção pode levar a:
  • Hepatite aguda e crónica
  • Cirrose
  • Carcinoma hepatocelular (CHC)

Proteínas virais

O RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure do vírus da hepatite C codifica:

• 3 proteínas estruturais:
  • Núcleo (contém RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure viral)
  • Envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology 1 ( E1 E1 An aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone, a major mammalian estrogen. It is converted from androstenedione directly, or from testosterone via estradiol. In humans, it is produced primarily by the cyclic ovaries, placenta, and the adipose tissue of men and postmenopausal women. Noncontraceptive Estrogen and Progestins) e envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology 2 (E2) no envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology lipídico
• 6 proteínas não estruturais (NS) (NS2, NS3, NS4A, NS4B, NS5A e NS5B)
  • Importantes na adesão, na replicação, na tradução e processamento de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure e na montagem e libertação virais
  • Alvos dos agentes antivirais mais MAIS Androgen Insensitivity Syndrome recentes

Regimes de tratamento

• Infeção aguda: anteriormente com interferão alfa (IFN-α) e ribavirina:
  • As recomendações atuais são semelhantes às do tratamento da infeção crónica por VHC (regime de antivíricos de ação directa).
  • Quando é detetada viremia Viremia The presence of viruses in the blood. Erythema Infectiosum, recomenda-se um regime pangenotípico.
  • Em certos locais onde o tratamento sem interferão não está disponível, o IFN-α continua a ser utilizado.
• Infeção crónica:
  • Dependente do genótipo, da presença de cirrose e se houve tratamento prévio
  • Tratamentos utilizados anteriormente:
    • IFN-α
    • Ribavirina
  • Agora substituído por antivirais de ação direta (DAVs, pela sigla em inglês):
    • Inibidores da protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS NS3/4A
    • Inibidores da NS5A
    • Inibidores da RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polimerase NS5B
  • Os antivirais de ação direta são habitualmente administrados em regime de terapêutica combinada.
    • > 90% de taxa de sucesso
    • Sem efeitos adversos significativos

IFN-α

Química

O interferão é uma proteína de sinalização pertencente à família das citocinas.

Mecanismo de ação

O IFN-α atua através de vários mecanismos:

• Induz sinais intracelulares responsáveis pela inibição do vírus:
  • Entrada na célula
  • Processamento de proteínas
  • Replicação
• Regula o sistema imune:
  • ↑ Expressão de moléculas de MHC
  • ↑ Atividade fagocítica
  • ↑ Sobrevivência, proliferação e atividade de células citotóxicas T CD8+ e células “natural killer” → lise das células infetadas

Farmacocinética

• Absorção:
  • Disponível nas formulações IV, IM e SC
  • Baixa biodisponibilidade oral
  • A absorção é lenta.
• Metabolismo: sofre proteólise por proteases Proteases Proteins and Peptides endógenas
• Excreção: renal e biliar

Indicações

• Hepatite:
  • Hepatite B crónica
  • Hepatite C
    • Aguda
    • Crónica (em combinação com a ribavirina)
  • Hepatite D crónica
  • Hepatite E crónica
• Neoplasias, como:
  • Linfoma não Hodgkin (LNH)
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma maligno
  • Leucemia de células em cabeleira ( HCL HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia, pela sigla em inglês)
  • Sarcoma de Kaposi Kaposi A multicentric, malignant neoplastic vascular proliferation characterized by the development of bluish-red cutaneous nodules, usually on the lower extremities, most often on the toes or feet, and slowly increasing in size and number and spreading to more proximal areas. The tumors have endothelium-lined channels and vascular spaces admixed with variably sized aggregates of spindle-shaped cells, and often remain confined to the skin and subcutaneous tissue, but widespread visceral involvement may occur. Hhv-8 is the suspected cause. There is also a high incidence in AIDS patients. AIDS-defining Conditions
  • Condylomata acuminata Condylomata Acuminata Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)
  • Linfoma folicular
• Outras doenças hematológicas:
  • Policitemia vera ( PV PV Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of rbcs. In addition, the wbc and platelet counts are also increased, which differentiate pv from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera)
  • Trombocitopenia essencial

Efeitos adversos

• Síndrome semelhante à gripe
  • Cefaleia
  • Febre e arrepios
  • Mialgia
  • Mal-estar
• ↑ transitório das enzimas hepáticas após 8-10 semanas de tratamento
• Se terapêutica prolongada:
  • Efeitos do SNC
    • Perturbações do humor Humor Defense Mechanisms
    • Convulsões
    • Confusão
    • Pensamentos suicidas
  • Supressão medular
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
    • Trombocitopenia
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Indução de autoanticorpos e doença autoimune
  • Infeções bacterianas/víricas/fúngicas graves
  • Doenças isquémicas e hemorrágicas

Contraindicações

• Doença hepática descompensada
• Doenças autoimunes
• História prévia de arritmia cardíaca
• Crises convulsivas não controladas
• Gravidez

Interações farmacológicas

• ↑ Níveis séricos de:
  • Metadona
  • Teofilina
• ↑ Risco de insuficiência hepática → didanosina
• ↑ Risco de mielossupressão com:
  • Zidovudina
  • Clozapina

Ribavirina

Química

• Análogo da guanosina
• Pró-fármaco → metabolizado na forma ativa no interior das células

Mecanismo de ação

• Assemelha-se à guanosina → interfere na síntese do trifosfato de guanosina (GTP, pela sigla em inglês)
• Inibe a polimerase dependente de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure viral de alguns vírus
• Resulta na inibição da:
  • Replicação viral ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure e RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure)
  • Síntese das proteínas virais

Farmacocinética

• Absorção:
  • Absorvido rapidamente
  • Biodisponibilidade:
    • ↑ com refeições ricas em gordura
    • ↓ com antiácidos
• Distribuição:
  • Amplamente distribuído
  • Não ligado a proteínas
• Metabolismo: hepático e intracelular (forma metabolitos ativos)
• Excreção:
  • Urina (primária)
  • Fezes

Indicações

• Hepatite viral:
  • Hepatite C crónica (em combinação com IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons)
  • Hepatite E crónica
• Infeção pelo vírus sincicial respiratório (VSR)
• Febres hemorrágicas virais específicas (como a febre de Lassa)

Efeitos adversos

• Prurido
• Distúrbios GI
• Depressão
• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica (AH) (dependente da dose)

Contraindicações

• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
• Doença cardiovascular significativa ( anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types grave → isquemia miocárdica)
• Disfunção renal grave
• Gravidez (teratogénico)

Interações farmacológicas

• ↑ Risco de toxicidade mitocondrial: didanosina
• Mielossupressão
  • Azatioprina
  • Zidovudina (sobretudo anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types)

Inibidores da Protease NS3A/4A

Fármacos desta classe

• Simeprevir Simeprevir Oral hcv-protease inhibitor effective against hepatitis C virus (hcv) serine protease ns3/4a. It is used in the treatment of chronic hepatitis C (antivirals) genotype 1 infection in adults with compensated liver disease, including cirrhosis. Antivirals for Hepatitis C (descontinuado nos Estados Unidos)
• Glecaprevir Glecaprevir Antivirals for Hepatitis C
• Grazoprevir Grazoprevir Antivirals for Hepatitis C
• Paritaprevir Paritaprevir Antivirals for Hepatitis C
• Voxilaprevir Voxilaprevir Antivirals for Hepatitis C

Mecanismo de ação

Os inibidores da protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS NS3A/4A são uma classe de fármacos que inibe a protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS de serina NS3/4A, necessária para a replicação do VHC.

Farmacocinética

• Distribuição: ligado a proteínas
• Metabolizado: enzimas do citocromo P450 (CYP) (principalmente CYP3A)
• Excreção: sobretudo nas fezes

Indicações

Os inibidores da protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS NS3A/4A são utilizados (geralmente em terapêutica combinada com outro DAV) no tratamento da hepatite C crónica.

Efeitos adversos

• Náuseas
• Cefaleia
• Fadiga
• Diarreia
• Erupções cutâneas e fotossensibilidade
• Descompensação hepática
• Reativação de hepatite B (testar VHB antes do tratamento do VHC)

Interações farmacológicas

• Pode aumentar o efeito hipoglicemiante de fármacos antidiabéticos
• ↑ Concentrações séricas de algumas estatinas
• Indutores e inibidores do CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) → altera os níveis de inibidores da protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS NS3A/4A

Inibidores da NS5A

Fármacos desta classe

• Daclatasvir Daclatasvir Antivirals for Hepatitis C (descontinuado nos Estados Unidos)
• Ledipasvir Ledipasvir Antivirals for Hepatitis C
• Velpatasvir Velpatasvir Antivirals for Hepatitis C
• Elbasvir Elbasvir Antivirals for Hepatitis C
• Ombitasvir Ombitasvir Antivirals for Hepatitis C
• Pibrentasvir Pibrentasvir Antivirals for Hepatitis C

Mecanismo de ação

• O mecanismo exato ainda não é conhecido.
• Liga-se a NS5A → inibe a replicação viral

Farmacocinética

• Absorção: habitualmente bem absorvido
• Distribuição: ligado a proteínas
• Metabolismo: A maioria é metabolizado pelo sistema CYP (geralmente CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)).
• Eliminação: principalmente nas fezes

Indicações

Estes fármacos são utilizados (geralmente em terapêutica combinada com outro DAV) no tratamento da hepatite C crónica.

Efeitos adversos

• Cefaleia
• Fadiga
• Náuseas
• Descompensação hepática
• Reativação de hepatite B (testar VHB antes do tratamento do VHC)

Interações farmacológicas

• Pode aumentar o efeito hipoglicemiante de fármacos antidiabéticos
• ↑ Concentrações séricas de algumas estatinas
• Indutores e inibidores de CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) → alteram os níveis dos inibidores da NS5A

Inibidores da RNA Polimerase Dependente de RNA NS5B

Classificação

• Inibidores da polimerase de nucleosídeos/nucleótidos (NPIs, pela sigla em inglês): sofosbuvir
• Inibidores não nucleosídeos da polimerase (NNPIs, pela sigla em inglês): dasabuvir

Mecanismo de ação

Os inibidores da RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polimerase dependente de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure NS5B têm como alvo a NS5B (uma polimerase de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure dependente de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure).

• Os NPIs são ativados nos hepatócitos → competem com nucleótidos e são incorporados no RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure viral → não podem ser adicionados novos nucleótidos → interrupção da replicação viral
• Os NNPIs ligam-se alostericamente à NS5B → ↓ função da polimerase → inibição da replicação viral

Farmacocinética

• Distribuição: ligado a proteínas
• Metabolismo:
  • NPIs fosforilados nos hepatócitos → forma ativa
  • Dasabuvir: CYP2C8 CYP2C8 A liver microsomal cytochrome p450 hydroxylase that oxidizes a broad spectrum of substrates including steroids, fatty acids, and xenobiotics. Examples of pharmaceutical substrates for cyp2c8 include; paclitaxol; torsemide; and; amodiaquine. Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) e CYP3A
• Excreção:
  • Sofosbuvir: principalmente na urina
  • Dasabuvir: principalmente nas fezes

Indicações

Os inibidores da RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polimerase dependente de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure NS5B são utilizados (geralmente em terapêutica combinada com outro DAV) no tratamento da hepatite C crónica.

Efeitos adversos

• Fadiga
• Cefaleia
• Insónias
• Náuseas
• Reativação da hepatite B

Interações farmacológicas

• Pode aumentar o efeito hipoglicemiante de fármacos antidiabéticos
• ↑ Concentrações séricas de algumas estatinas
• Amiodarona → ↑ bradicardia (com sofosbuvir)