Farmaci antivirali: Definizione

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1 Farmaci antivirali: Definizione
Un virus è un agente infettivo di dimensioni submicroscopicche che è incapace di crescere o riprodursi al di fuori della cellula ospite.

2 Struttura Geni (DNA o RNA) (Tutti) Rivestimento proteico (Tutti)
Rivestimento lipidico (Alcuni quando sono fuori della cellula)

3 Virus a DNA La replicazione del genoma virale della maggior parte dei virus a DNA avviene nel nucleo della cellula. Virus a RNA La replicazione dell’RNA virale avviene nel citoplasma Virus a trascrizione inversa Questi virus replicano il loro RNA attraverso la trascrittasi inversa ovvero da RNA formano DNA.

4 Struttura

5 Struttura Icosaedrica Avvolti in membrana

6 DIVERSITA’ GENOMICA TRA VIRUS Propriertà Parametri
Acid Nucleico DNA RNA Both DNA and RNA (at different stages in the life cycle) Forma Linear Circular Segmented Tipo filamenti Single-stranded Double-stranded Double-stranded with regions of single-strandedness Senso Positive sense (+) Negative sense (−) Ambisense (+/−)

7 Definizione La Sindrome da immuno-deficienza acquisita (AIDS) è una malattia del sistema immunitario umano causata dal virus dell’immunodeficienza umana (HIV)

8 Caratteristiche The main change from the Bangui definition is the addition of an HIV test for HIV antibody. If this test gives a positive result and one or more of the following conditions, the individual is considered to have AIDS. 1) > 10% body weight loss or cachexia, with diarrhoea or fever, or both, intermittent or constant for at least 1 month, not known to be due to a condition unrelated to HIV infection. 2) cryptococcal meningitis 3) pulmonary or extra-pulmonary tuberculosis 4) Kaposi's sarcoma 5) neurological impairment that is sufficient to prevent independent daily activities, not known to be due to a condition unrelated to HIV infection (for example, trauma, or cerebrovascular accident). 6) candiasis of the oesophagus (which may be presumptively diagnosed based on the presence of oral candiasis accompanied by dysphagia. 7) clinically diagnosed life-threatening or recurrent episodes of pneumonia, with or without etiological confirmation 8) invasive cervical cancer

9 Caratteristiche < 200 cellule linfoidi CD4/ml di sangue umano

10 The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts <350 cells/mm3 . Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts between 350–500 cells/mm3. Treatment for patients with CD4 cell counts >500 cells/mm3 is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data are not available, and the risk of antiretroviral toxicities, resistance, nonadherence, and cost should be considered in individual patients.

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12 First contact The HIV-1 envelope (Env) protein is a type I integral membrane protein that mediates viral attachment and membrane fusion and is also the target for neutralizing antibodies. Synthesized as a single polypeptide precursor that forms trimers, Env is subsequently cleaved by a cellular protease to generate two noncovalently associated subunits, gp120 and gp41. The gp120 binds virus to the cell surface, whereas the membrane-spanning gp41 subunit is largely responsible for membrane fusion. The primary receptor for HIV-1 is CD4, explaining the propensity of this virus to infect certain T cells and macrophages, ultimately leading to immune dysfunction. Although CD4 binding is a prerequisite for HIV-1 entry, attachment of virus per se may be mediated by an impressive list of molecules that may serve to concentrate virus on the cell surface and increase the frequency of Env-receptor interactions. The most striking example of an attachment molecule is DCSIGN, a type II membrane protein with a mannose-binding, C-type lectin domain found on some types of dendritic cells (DCs). DC-SIGN captures HIV-1 to the surface of the DC, retaining it in a native, infectious form that can be efficiently presented to permissive CD4-positive T cells, resulting in enhanced infection. GENES & DEVELOPMENT 14:2677–2688

13 MECCANISMO DI AZIONE 1o step

14 Il primo step può essere suddiviso in tre sottosteps:
1.Interazione della glicoproteina virale gp120 con il recettore CD4 del linfocita-T 2. Interazione del virus con i corecettori presenti sulla cellula ospite (CCR5 e CXCR4) 3. Fusione del virus con la membrana della cellula ospite mediata dalla proteina virale gp41 Possibili farmaci: Antagonisti recettoriali delle chemochine Inibitori della fusione virale

15 Inibitori della fusione del virus al linfocita
Fusion or attachment inhibitor CD4/T-cell HIV Farmaci: - Enfuvirtide

16 1) TAK-220 2) SCH-D 3) UK-427857 4) GW873140 KRH-1636 AMD3100 AMD070
Antagonisti delle Chemochine (CCR5 inhibitors) (Nessuno ancora approvato dalla FDA) 1) TAK-220 2) SCH-D 3) UK 4) GW873140 Antagonisti delle Chemochine (CXCR4 inhibitors) (Nessuno ancora approvato dalla FDA) KRH-1636 AMD3100 AMD070

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18 2o step

19 Struttura chimica Nucleoside/nucleotide

20 Reverse transcriptase
Inibitori nucleosidici della transcrittasi inversa Farmaci: Zidovudina Stavudina Zalcitabina Didanosina Lamuvidina Abacavir Emtricitabina NRTI or NNRTI HIV instructions Reverse transcriptase enzyme Zidovudina

21 Reverse transcriptase
Inibitori nucleotidici della transcrittasi inversa Farmaci: - Tenofovir NRTI or NNRTI HIV instructions Reverse transcriptase enzyme

22 Meccanismo di azione inibitori trascrittasi inversa

23 [Braz J Infect Dis 2011;15(2):151-155]
Highly active antiretroviral therapy (HAART) reduces AIDS-related morbidity and mortality, however it has been associated with metabolic abnormalities. This study estimated the prevalence of lipid abnormalities and related factors among patients on HAART. A cross-sectional study was conducted on adult patients, in central Brazil. Patients were interviewed, and blood obtained for lipids measurement. Dyslipidemia was defined as total cholesterol (TC) ≥ 240 mg/dL, low-density lipoprotein (LDL) ≥ 160 mg/dL, triglycerides (TG) > 200 and/or high-density lipoprotein (HDL) < 40 mg/dL. Multiple logistic regression analyses were performed (SPSS 13.0). One hundred and thirteen patients were recruited. Mean age was 39.3 years; 68.1% were males; 50.4% were on nucleoside reverse transcriptase inhibitors (NRTI) in combination with non-nucleoside reverse transcriptase inhibitors (NNRTI), while 42.5% were on NRTI in combination with protease inhibitors (PIs). The prevalence of dyslipidemia was 66.7%. Low HDL was the most frequent abnormality (53.5%), followed by high TG (36.1%). Patients on a PI regimen had a 5.2-fold higher risk (95% CI: ) of dyslipidemia, even after adjusting for sex, age, and duration of HIV infection/AIDS. The study discloses a high prevalence rate of dyslipidemia and points out a need for intervention programs to reduce future cardiovascular events in patients, on HAART.

24 INIBITORI DELLA TRASCRITTASI INVERSA NON NUCLEOSIDICI
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz;

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27 3o step

28 Inibitori dell’integrasi
Farmaci: FDA approval of Isentress (raltegravir) The Food and Drug Administration (FDA), on October 12, 2007, Expert Opin Investig Drugs. 2011 Apr;20(4): Epub 2011 Mar 8. S/GSK , a new integrase inhibitor for the treatment of HIV: promises and challenges. Lenz JC, Rockstroh JK. University of Bonn, Medicine I, Bonn, Germany INTRODUCTION: The recent introduction of integrase inhibitors (INIs) into the HIV treatment armentarium has had a significant impact on HIV treatment. However, at present, raltegravir twice daily is the only licensed INI featuring a lower genetic barrier compared with boosted protease inhibitors. S/GSK represents a new INI in current development. It is a once-daily, unboosted INI with low pharmacokinetic variability and predictable exposure-response relationship. Phase IIb studies in antiretroviral-naïve patients have demonstrated non-inferiority to efavirenz-based HIV therapy. Phase II studies in INI-experienced patients show partially retained activity in vivo. Overall, the safety profile of S/GSK in all studies completed has been very favorable. AREAS COVERED: A Pubmed and Medline search was carried out on all articles on S/GSK from 2005 to 2010, including recent abstract presentations from major HIV conferences (CROI 2010, WAC2010, EACS2009, HIV10 and ICAAC2010). The reader will become acquainted with the unique properties of this new INI and will understand the current promises and challenges of the data available from S/GSK EXPERT OPINION: S/GSK represents a new, unboosted, once-daily INI in development with distinct pharmacokinetics and resistance profile, which has showed promising potency and tolerability in the first clinical studies.

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31 Raltegravir in treatment naive patients.
Eur J Med Res. 2009 Nov 24;14 Suppl 3:22-9. Raltegravir in treatment naive patients. Cossarini F, Castagna A, Lazzarin A. Department of Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 60, Milano, Italy. Raltegravir is the first integrase inhibitor approved for the treatment of HIV infection based on the superior efficacy it showed compared to optimized backbone therapy alone in patients harboring multidrug resistant viruses. Studies on naive patients showed comparable efficacy of raltegravir and efavirenz and just recently the US Food and Drug Administration (FDA) approved raltegravir for the use in naive patients based on the favorable results of the international double-blind phase III STARTMRK trial. Additional interesting findings were the faster, and not yet explained, decay of HIV-1 RNA and the higher CD4+ cells increase in the raltegravir group as compared to the efavirenz group. Raltegravir is generally well tolerated and adverse events were generally similar in raltegravir and comparator arms throughout all studies. When compared to efavirenz, patients on raltegravir showed less incidence of central nervous system-related adverse events. In studies on experienced patients higher incidence of cancers was found in the raltegravir arm: a relationship with the drug was, however not confirmed in a recent review considering all raltegravir studies. Raltegravir also showed a safe lipid profile especially in naive patients, finding that renders the drug attractive for patients with other cardiovascular risk factors. All this characteristics in association with its specific mechanism of action, make raltegravir an interesting drug for naive patients and a large use in this type of patients is predictable. Only time and experience, however, will tell us whether raltegravir will maintain its promises in the long run.

32 Genoma virale Vpr = Gene che codifica una proteina virale che favorisce l’ingresso del DNA virale dal citoplasma al nucleo della cellula dell’ospite

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35 4o step

36 4o step La trascrizione del DNA in RNA virale nel nucleo della cellula ospite è facilitato dalla proteina Nef Non ci sono ancora inibitori di questa proteina

37 The Nef protein is an accessory gene product of HIV and SIV that is dispensable for virus spread in experimental ex vivo cell culture systems. In infected patients or monkeys however, Nef is critical for high virus replication and disease progression. In fact, defects in the nef gene lead to slowly progressing or even asymptomatic infections and transgenic mice expressing Nef as the only HIV-1 gene product develop AIDS-like disease .

38 5o step Sarà molto difficile interferire con questa via perchè le proteine coinvolte in questo meccanismo sono di importanza vitale per la cellula ospite.

39 6o step

40 6o step Per essere pienamente infettivi i virioni devono maturarsi, un processo che coinvolge la rottura di proteine virali quali il Gag e Gag-Pol attraverso l’ HIV proteasi. Inibitori delle proteasi hanno mostrato un grande successo in pazienti specialmente in combinazione con gli inibitori della trascrittasi inversa.

41 Gli inibitori della proteasi sono molto cari da produrre ed inducono molti effetti collaterali indesiderati. Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir Lopinavir Atazanavir Fosamprenavir Tipranavir Darunavir Il costo del Darunavir è di 9000 dollari per un anno di trattamento

42 Name Trade name Company Patent Notes Saquinavir Fortovase, Invirase Hoffmann–La Roche U.S. Patent 5,196,438 It was the first protease inhibitor approved by the FDA (December 6, 1995). Ritonavir Norvir Abbott Laboratories U.S. Patent 5,541,206 - Indinavir Crixivan Merck & Co. U.S. Patent 5,413,999 Nelfinavir Viracept Japan Tobacco U.S. Patent 5,484,926 Amprenavir Agenerase GlaxoSmithKline U.S. Patent 5,585,397 The FDA approved it April 15, 1999, making it the sixteenth FDA-approved antiretroviral. It was the first protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra Abbott Is only marketed as a combination, with ritonavir. Atazanavir Reyataz Bristol-Myers Squibb The FDA approved it on June 20, Atazanavir was the first PI approved for once-daily dosing. It appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs. Fosamprenavir Lexiva, Telzir Is a pro-drug of amprenavir. The FDA approved it October 20, The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reduces the number of pills required versus standard amprenavir. Tipranavir Aptivus Boehringer-Ingelheim Also known as tipranavir disodium Darunavir Prezista Tibotec It was approved by the Food and Drug Administration (FDA) on June 23, Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents[3]. Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv combination being superior to the lopinavir/rtv combination for first-line therapy.[4] Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.[5][6][7]

43 2. Iperlipidemia (aumento del colesterolo e trigliceridi)
Effetti collaterali (indinavir) 1. Calcoli renali 2. Iperlipidemia (aumento del colesterolo e trigliceridi) 3. Lipodistrofia Pazienti con malattie strutturali a livello cardiaco devono usare il lopinavir/ritonavir con cautela

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45 Effetti collaterali dovuti a variazioni genetiche
1) Forte associazione tra reazioni di ipersensibilità da abacavir e lo human leukocyte antigen HLA-B*5701 2) Alleli del CYP2B6 ed efavirenz in effetti collaterali a livello del sistema nervoso centrale 3) Alleli dell’ UGT1A1 ed iperbilirubinemia associata alla somministrazione di atazanavir (This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites) 4) Aumenti dell’allele HLA-DRB*0101 della classe II dell’ HLA class II nell’ipersensibilità da nevirapine.

46 Linee Guida degli USA

47 Obiettivi delle linee guida:
Definire la base di partenza in ogni paziente Obiettivi del trattamento Indicazioni per l’inizio della terapia antiretrovirale Scelta del regime iniziale di pazienti naive al trattamento farmacologico Farmaci o combinazioni da evitare Management di eventi avversi e delle interazioni farmacologiche Management dell’insuccesso farmacologico Considerazioni speciali in popolazioni di pazienti particolari

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49 What to Start in Antiretroviral-Naïve Patients
Linee guida 2008 What to Start in Antiretroviral-Naïve Patients Protease Inhibitor–Based Regimens: • Once-daily ritonavir-boosted darunavir has been added as a preferred PI component (AI). • Once-daily ritonavir-boosted lopinavir has been moved from alternative to preferred PI component (except for pregnant women) (AI). Dual-NRTI Options: • Abacavir + lamivudine has been moved from a preferred to an alternative dual-NRTI component because of concerns regarding an increased risk of myocardial infarction in patients with high cardiac risk factors, as suggested by large observational cohort studies, and concerns regarding virologic potency in patients with baseline viral loads >100,000 copies/mL (BI). Combinations Not to Use or to Use with Caution: • A combination of unboosted atazanavir + didanosine + emtricitabine (or lamivudine) is not recommended because of efficacy concerns (BI). • A combination of nevirapine + tenofovir + emtricitabine (or lamivudine) should be used with caution and with close monitoring of virologic responses because of reports of early virologic failure in several small studies (CII).

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53 Linee guida Italiane Lamivudina (3TC) Emtricitabina (FTC)
Abacavir (ABC) Didanosina ddI) Emtricitabina (FTC) Tenofovir (TDF)

54 Linee guida del Sud Africa
Le linee guida raccomandano: 1) Inibitori non nucleosidici della trascrittasi inversa (NNRTI) (Nevirapina, Delavirdina, Efavirenz) 2) Inibitore delle proteasi (Ritonavir) combinato con due inibitori nucleosidici della trascrittasi inversa (NRTIs)

55 Virus a DNA Virus a DNA a doppia elica: Virus a DNA a singola elica:
Un virus a DNA è un virus il cui materiale genetico è il DNA e usa una DNA polimerasi DNA dipendente per replicasi. L’acido nucleico è generalmente a doppia elica ma può essere anche ad una singola catena. Virus a DNA a doppia elica: Adenoviruses, Herpesviruses, Poxviruses Virus a DNA a singola elica: Parvoviruses)

56 Human Herpesvirus (HHV) classification[1][7]
Type Synonym Subfamily Primary Target Cell Pathophysiology Site of Latency Means of Spread HHV-1 Herpes simplex virus-1 (HSV-1) α (Alpha) Mucoepithelial Oral and/or genital herpes (predominantly orofacial), as well as other herpes simplex infections Neuron Close contact HHV-2 Herpes simplex virus-2 (HSV-2) α Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections Close contact (sexually transmitted disease) HHV-3 Varicella zoster virus (VZV) Chickenpox and shingles Respiratory and close contact HHV-4 Epstein-Barr virus (EBV), lymphocryptovirus γ (Gamma) B cells and epithelial cells Infectious mononucleosis, Burkitt's lymphoma, CNS lymphoma in AIDS patients, B cell Close contact, transfusions, tissue transplant, and congenital post-transplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy leukoplakia HHV-5 Cytomegalovirus (CMV) β (Beta) Monocyte, lymphocyte, and epithelial cells Infectious mononucleosis-like syndrome,[9] retinitis, etc. Monocyte, lymphocyte, and ? Saliva HHV-6 Roseolovirus, Herpes lymphotropic virus β T cells and ? Sixth disease (roseola infantum or exanthem subitum) Respiratory and close contact? HHV-7 Roseolovirus  ? HHV-8 Kaposi's sarcoma-associated herpesvirus γ Lymphocyte and other cells Kaposi's sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease Close contact (sexual (KSHV), a type of rhadinovirus

57 L’epatite B è una malattia causata dal virus dell’epatite B (HBV) il quale infetta il fegato dell’uomo e causa un’infiammazione chiamata epatite. L’epatite acuta causa vomito, itterizia e raramente morte. L’epatite B cronica può causare cirrosi epatica e cancro del fegato il quale non risponde ai comuni chemioterapici. L’infezione e prevenibile attraverso la vaccinazione. Entecavir è un analogo nucleosidico della guanina che inibisce la trascrittasi inversa, la replicazione del DNA e la trascrizione nel processo di replicazione del virus. Adefovir è un inibitore della trascrittasi inversa analogo nucleotidico somministrato per via orale(NtRTI).

58 Gli interferoni (IFNs) sono delle proteine prodotte dalle cellule del sistema immunitario di molti vertebrati in risposta a stimoli indotti da virus, parassiti e cellule tumorali. Essi appartengono alla classe delle glicoproteine conosciute come citochine e sono prodotti da una varietà di cellule in risposta alla presenza di RNA a doppia elica, un indicatore importante dell’infezione virale. Gli interferoni assistono il sistema immunitario inibendo la replicazione virale dentro la cellula ospite attivando le cellule Natural Killer, I macrofagi e aumentando la presenza antigenica per I linfociti T e aumentando la resistenza della cellula ospite all’infezione virale.

59 Farmaci antivirali per virus a DNA
Aciclovir Valganciclovir Famciclovir 2 3 1

60 Farmaci antivirali per virus a DNA

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62 Meccanismo di azione L’Acyclovir è un nucleoside purinico con attività inibitoria dell’ herpes simplex virus tipo 1 (HSV-1), 2 (HSV-2), e varicella-zoster virus (VZV). L’aciclovir trifosfato ferma la replicazione del DNA virale attraverso l’inibizione competitiva della DNA polimerasi, l’incorporazione e la terminazione della crescita della catena di DNA virale.

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65 Virus dell’epatite C

66 Le epatiti virali raggruppano diverse infezioni che colpiscono il fegato. Sono noti 5 tipi di epatite : A , B, C, D(delta) ed E. E’ un’infiammazione del fegato causata da un virus chiamato HCV, un flavovirus. HCV è un virus positivo a filamento di RNA con diverse pro-proteine non strutturali, che rappresentano il target per lo sviluppo dei farmaci. Nel 25% dei casi l’infezione da HCV è acuta, cioè il virus subito dopo il contagio, viene eliminato dal nostro sistema immunitario in poche settimane. Dopo l’infezione acuta circa il 20-40% guarisce mentre il restante 60-80% evolve verso l’epatite cronica, portando la maggior parte dei soggetti infetti a sviluppare cirrosi ed epatocarcinoma

67 La terapia attuale (terapia standard) prevede l’utilizzo di interferone pegilato e ribavirina.
Può durare da sei mesi, per i genotipi 2 e 3, ad un anno, per i genotipi 1 e 4.

68 Drugs Today 2011, 47(10): 743 Boceprevir Rizza, S.A., Talwani, R., Nehra, V., Temesgen, Z. Boceprevir is a hepatitis C virus (HCV) serine protease NS3 inhibitor that has recently been approved by the U.S. Food and Drug Administration, the European Medicines Agency and Health Canada for the treatment of chronic genotype 1 HCV infection. It has potent in vitro antiviral activity against HCV genotypes 1a and 1b and is primarily metabolized via the aldoketoreductase pathway with minor cytochrome P450 3A4 metabolism. Boceprevir is well tolerated with few drug-drug interactions which are easy to manage; no dose adjustment is required in patients with hepatic or renal impairment. Phase I trials of boceprevir demonstrated favorable pharmacokinetic, metabolic and safety profiles. Phase II and III trials of boceprevir confirmed the antiviral activity of the drug and its use at a dose of 800 mg three times daily. Clinical trials in treatment-naive and previously treated HCV-infected patients demonstrated a 26% and 45% (respectively) improvement in sustained viral response when boceprevir was added to standard pegylated interferon and ribavirin anti-HCV therapy. Boceprevir is the first-in-class of an exciting new phase of HCV treatment