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

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Presentation on theme: "Un virus è un agente infettivo di dimensioni submicroscopicche che è incapace di crescere o riprodursi al di fuori della cellula ospite. Definizione Farmaci."— Presentation transcript:

1 Un virus è un agente infettivo di dimensioni submicroscopicche che è incapace di crescere o riprodursi al di fuori della cellula ospite. Definizione Farmaci antivirali: BacteriaVirus Larger (1000nm)Smaller ( nm)

2 Alcuni dei virus piu’ conosciuti

3 Struttura del virus - Geni (DNA o RNA) (Tutti) - Rivestimento proteico (Tutti) - Rivestimento lipidico (Alcuni quando sono fuori della cellula)

4 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.

5 Struttura

6 Icosaedrica Avvolti in membrana

7 DIVERSITA’ GENOMICA TRA VIRUS PropriertàParametri 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 (+/−)

8 The DNA strand orientation is by convention 5' → 3'. This concept allows to determine, for a given gene, the gene orientation relative to the 5' → 3' DNA strand. sense: same direction antisense: opposite direction

9 I: dsDNA virusesHerpesviridae (HSVI-II, VZV, CMV) Papillomavirus (HPV) II: ssDNA viruses Parvoviridae III: dsRNA virusesRotavirus IV: (+)ssRNA virusesHepatitis C virus, Yellow fever virus V: (−)ssRNA virusesInfluenzavirus A, Influenzavirus B, Ebola virus, Measles virus, Mumps virus, Rabies virus, Respiratory Syncytial Virus (RSV) VI: ssRNA-RT virusesHIV VII: dsDNA-RT virusesHepadnaviridae (hepatitis B virus) Baltimore classification of viruses

10 Some human diseases caused by viruses AIDSBurkitt's lymphoma chicken pox colds Colorado tick fever dengue encephalitis fever blisters genital warts gastroenteritis genital herpes German measles hepatitis influenza leukemia liver cancer measles mononucleosis mumps oral herpes polio rabies shingles smallpox virus hemorrhagic fever warts yellow fever

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

14 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.testantibody 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.diarrhoeafever 2) cryptococcal meningitismeningitis 3) pulmonary or extra-pulmonary tuberculosistuberculosis 4) Kaposi's sarcomaKaposi'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. candiasis 7) clinically diagnosed life-threatening or recurrent episodes of pneumonia, with or without etiological confirmation 8) invasive cervical cancer

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

16 Structure of HIV The figure below shows a cross-sectional diagram of the HIV virion [53]. Each virion expresses 72 glycoprotein projections composed of gp120 (orange) and gp41 (light blue). Gp41 is a transmembrane molecule that crosses the lipid bilayer of the envelope. Gp120 is non-covalently associated with gp41 and serves as the viral receptor for CD4 on host cells. The viral envelope also contains some host-cell membrane proteins such as class I and class II MHC molecules. Within the envelope is the viral core, or nucleocapsid, which includes a layer of a protein called p17 (green) and an inner layer protein called p24 (yellow). The HIV genome consists of two copies of ssRNA, which are associated with two molecules of reverse transcriptase p64 (light red) and nucleoid proteins p10, a protease (red), and p32, an integrase (dark blue).

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18 CD4 cell = T cell with CD4 receptor that recognizes antigens on the surface of a virus-infected cell and secretes lymphokines that stimulate B cells and killer T cells; CD4 is a cell-surface glycoprotein found on the mature helper T cells and immature thymocytes, as well as on monocytes and macrophages. Normally, about 65% of T cells in the blood are CD4+ (have CD4 protein protruding from their membrane).helper T cells

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20 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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25 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

26 1 o step MECCANISMO DI AZIONE

27 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: 1)Antagonisti recettoriali delle chemochine 2)Inibitori della fusione virale

28 - Enfuvirtide Membrana virale Membrana linfocita Inibitori della fusione del virus al linfocita

29 CCR5 antagonisti Maraviroc is the first US Food and Drug Administration–approved drug from a new class of antiretroviral agents that targets a host protein, the chemokine receptor CCR5, rather than a viral target. Binding of maraviroc to this cell- surface protein results in blocking human immunodeficiency virus type 1 (HIV-1) attachment to the coreceptor and prevents the virus from entering CD4+ cells.

30 CCR5 was initially identified as a seven-transmembrane receptor for the chemokines RANTES, MIP-1, and MIP-1 (Combadiere et al., 1996). The receptor is a 352-amino acid protein that belongs to the class A G protein-coupled receptor family with a high homology to rhodopsin and is most likely coupled to G proteins of the Gi/o subfamily because its activation in cells leads to inhibition of cAMP production, stimulation of Ca2 ion release, and activation of mitogen-activated protein kinase family members (Onuffer and Horuk, 2002). CCR5 activation can also lead to phosphorylation of the Jak-Stat pathway, suggesting that the receptor could signal through other pathways in addition to the classic G protein-coupled mechanisms (Wong and Fish, 2003). In the immune system CCR5 is expressed mainly on effector/ memory T cells, monocytes, and dendritic cells, and its expression is up-regulated by activation (Lee et al., 1999). It is noteworthy that CCR5 is a coreceptor for HIV-1. The virus entry into human hematopoetic cells in vivo requires the cooperation of the viral subunit envelope glycoproteins gp120 and gp41, and two host-cell proteins, the CD4 receptor and either the CCR5 and CXCR4 coreceptor (Zhang and Moore, 1999). Binding of the viral envelope protein (Env) to CD4 induces conformational changes in the gp120 subunit that enable it to interact efficiently with the CCR5 or CXCR4 coreceptor (Wu et al., 1996). Although the structural consequences of coreceptor binding are not well understood, it is clear that CCR5 is essential for viral transmission and replication during the early, clinically latentphase of disease (Gonzalez et al., 2001). CCR5 receptors role in HIV infection JPET 338:228–239, 2011

31 Neuropatia da vicriviroc

32 Reduced expression of CCR5 on target CD4+ cells lowers their susceptibility to infection by R5-tropic HIV-1, potentially preventing transmission of infection and delaying disease progression. Binding of the HIV-1 envelope (Env) protein gp120 with CCR5 is essential for the entry of R5 viruses into target cells.

33 Three-Year Safety and Efficacy of Vicriviroc, a CCR5 Antagonist, in HIV-1-Infected, Treatment-Experienced Patients J Acquir Immune Defic Syndr August 15; 54(5): 470–476. Abstract Background—Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods—Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10 or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results—118 subjects were randomized. Virologic failure (<1 log10 decline in HIV-1 RNA ≥16 weeks post-randomization) occurred by week 48 in 24/28 (86%), 12/30 (40%), 8/30 (27%), 10/30 (33%) of subjects randomized to placebo, 5, 10 and 15 mg respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies/mL within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events. Conclusions—Vicriviroc appears safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection.

34 2 o step

35 Struttura chimica Nucleoside/nucleotide

36 Inibitori nucleosidici della transcrittasi inversa

37 Inibitori nucleotidici della transcrittasi inversa Farmaci: - Tenofovir Quando una cellula viene infettata da retrovirus, l’RNA viene copiato in una molecola di DNA a doppio filamento proprio grazie alla trascrittasi inversa presente nel virione che entra nella cellula infettata assieme all’RNA. Meccanismo di azione inibitori trascrittasi inversa

38 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. [Braz J Infect Dis 2011;15(2): ]

39 Abstract Background: The use of highly active antiretroviral therapy (HAART) as the main option for management of people living with Human Immune deficiency virus (HIV) is associated with decrease morbidity and mortality. This is due to its effectiveness in inhibiting viral replication. However this effectiveness is not without adverse drug effects which in many settings are not monitored. Methods: A cross sectional clinical chart review of adult Cameroonian patients on HAART between 2003 and 2009 at the Douala General Hospital was done in search of reported HAART-associated Adverse Drug effects (ADRs). The prevalence of ADR defined as the proportion of the study population with ADR was determined and stratified by age, sex, weight and HAART regimen. Results: Sixty-six (19.5%) of the 339 patients on HAART reported ADRs. Among those who reported ADRs, 29.6% were on D4T-3TC-EFV, 29.3% on D4T-3TC-NVP, 16% on AZT-3TC-EFV and 10.8% on AZT-3TC-NVP. Peripheral Neuropathy was the most common ADR and represented 21.2% of all ADRs. Patients on D4T containing regimens were more likely to develop ADR (OR = 3.5, 95% CI 1.5 – 9.8, p<0.01) and 56.1% of all ADRs were associated to D4T. Hospital admissions were for patients with severe anaemia, no fatal cases of ADRs were recorded. Conclusion: HAART-associated ADRs are common and therefore should be actively looked for by caregivers so as to ameliorate the quality of life of HIV patients on treatment. Pan African Medical Journal. 2012; 12:87 Henry Namme Luma1,2,&, Marie-Solange Doualla1,2, Simeon-Pierre Choukem1,3, Elvis Temfack1, Gloria Ashuntantang2,4, Henry Achu Joko1, Sinata Koulla-Shiro2 1Department of Internal Medicine, Douala General Hospital, Douala, Cameroon, 2Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon, 3Depatment of Clinical Sciences, Faculty of Health Sciences, University of Buea, Buea, Cameroon, 4Department of Internal Medicine, Yaoundé General Hospital, Yaoundé, Cameroon

40 ADR reactions %

41 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;reverse transcriptase inhibitorsHIV-1 reverse transcriptasenevirapinedelavirdineefavirenz INIBITORI DELLA TRASCRITTASI INVERSA NON NUCLEOSIDICI

42 Etravirine: Etravirine (TMC125) is a second-generation NNRTI, which was recently approved by the FDA for treatment-experienced patients with resistance to an NNRTI and other antiretroviral agents (figure 1b). Etravirine, administered with or without a protease inhibitor or enfuvirtide, is the first NNRTI to show clinical efficacy after 24 weeks in patients who have demonstrated failure to respond to treatment with both a protease inhibitor and either nevirapine or efavirenz. Non-Nucleoside Reverse Transcriptase Inhibitors Rilpivirine Rilpivirine (TMC278) is a diarylpyrimidine compound with a higher genetic barrier to resistance compared with currently approved NNRTIs. This high genetic barrier may be due in part to its internal flexibility, enabling it to adjust its configuration in HIV-1 reverse transcriptase in the presence of mutations.

43 Vol. 36 No. 6 June 2011 P&T®

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45 3 o step After entry into cells, retroviral genomic RNA (vRNA) is reverse transcribed into DNA (vDNA) by RT. Then, vDNA is transported into the nucleus (nuclear import) and finally integrated into host chromosomal DNA (black lines) Frontiers in Microbiology | Virology October 2011 | Volume 2 | Article 210

46 Quashie et al. BMC Medicine 2012, 10:34 RAL=Raltegravir; EVG= Elvitegravir ; DTG= Dolutegravir

47 Novel therapeutic strategies targeting HIV integrase The first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Quashie et al. BMC Medicine 2012, 10:34

48 Expert Opin Investig Drugs.Expert Opin Investig Drugs Apr;20(4): Epub 2011 Mar 8. S/GSK ( Dolutegravir ), a new integrase inhibitor for the treatment of HIV: promises and challenges. 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 ( Dolutegravir ) represents a new INI in current development. I t 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.

49 Eur J Med Res. Eur J Med Res Nov 24;14 Suppl 3:22-9. Raltegravir in treatment naive patients. Cossarini FCossarini F, Castagna A, Lazzarin A. 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.

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

51 LTR = long terminal repeats Gag = group specific antigen Pol = DNA polimerase Vpr = viral protein R Env = Envelop protein Nef = Negative Regulatory Factor Vif = Viral infectivity factor Vpu = Viral Protein U Rev = Regulator of Virion Expression Tat = Trans-Activator of Transcription

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54 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 4 o step

55 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.

56 5 o step Sarà molto difficile interferire con questa via perchè le proteine coinvolte in questo meccanismo sono di importanza vitale per la cellula ospite.

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58 6 o step

59 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. 6 o step

60 HIV-1 Assembly, Budding, and Maturation Wesley I. Sundquist Wesley I. Sundquist 1 and Hans-Georg Kräusslich 2Hans-Georg Kräusslich 1 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany Virion morphogenesis can be divided into three stages: assembly, wherein the virion is created and essential components are packaged; budding, wherein the virion crosses the plasma membrane and obtains its lipid envelope; and maturation, wherein the virion changes structure and becomes infectious. All of these stages are coordinated by the Gag polyprotein.

61 Gli inibitori della proteasi sono molto cari da produrre ed inducono molti effetti collaterali indesiderati. 1)Saquinavir, 2)Ritonavir, 3)Indinavir, 4)Nelfinavir, 5)Amprenavir 6)Lopinavir 7)Atazanavir 8)Fosamprenavir 9)Tipranavir 10) Darunavir Il costo del Darunavir è di 9000 dollari per un anno di trattamento

62 All PIs, with the exception of tipranavir, are competitive peptidomimetic inhibitors, mimicking the natural substrate of the viral proteasi. Meccanismo di azione

63 NameTrade name CompanyPatentNotes SaquinavirFortovase, Invirase Hoffmann–La Roche U.S. Patent 5,196,438 It was the first protease inhibitor approved by the FDA (December 6, 1995).FDADecember RitonavirNorvirAbbott Laboratories U.S. Patent 5,541,206 - IndinavirCrixivanMerck & Co.U.S. Patent 5,413,999 - NelfinavirViraceptJapan TobaccoU.S. Patent 5,484,926 - AmprenavirAgeneraseGlaxoSmithKlineU.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.April December LopinavirKaletraAbbott-Is only marketed as a combination, with ritonavir.ritonavir AtazanavirReyatazBristol-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.June FosamprenavirLexiva, Telzir GlaxoSmithKline-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.October slow-release TipranavirAptivusBoehringer- Ingelheim -Also known as tipranavir disodium DarunavirPrezistaTibotec-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]Food and Drug AdministrationJune OARAC [3]phase IIIrtv lopinavirrtv [4]leapfrogged [5][6][7]

64 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

65 MA, Matrix; CA, Capsid; NC, Nucleocapsid;

66 Maturation Inhibitors Bevirimat (PA 457) Bevirimat (PA 457) is the first compound in the novel class of antiretrovirals called maturation inhibitors, and it is currently in phase II development (figure 1i). Bevirimat inhibits HIV-1 gag processing, which blocks conversion of p25 to p24, a viral core protein. This results in defective viral core condensation and noninfectious viral particles. In essence, this compound is a protease inhibitor, but rather than directly inhibiting the enzyme, bevirimat attaches to the cleavage site of gag between the capsid protein and SP1.

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69 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. Effetti collaterali dovuti a variazioni genetiche

70 Linee Guida degli USA

71 Obiettivi delle linee guida: 1)Definire la base di partenza in ogni paziente 2)Obiettivi del trattamento 3)Indicazioni per l’inizio della terapia antiretrovirale 4)Scelta del regime iniziale di pazienti naive al trattamento farmacologico 5)Farmaci o combinazioni da evitare 6)Management di eventi avversi e delle interazioni farmacologiche 7)Management dell’insuccesso farmacologico 8)Considerazioni speciali in popolazioni di pazienti particolari

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73 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). Linee guida 2008

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

78 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)

79 Virus a DNA 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: AdenovirusesAdenoviruses, Herpesviruses, PoxvirusesHerpesvirusesPoxviruses Virus a DNA a singola elica: ParvovirusesParvoviruses)

80 Life cycle of hepatitis B virus (HBV)

81 Clin Invest Med.Clin Invest Med Oct;19(5): Therapy for chronic viral hepatitis. Alvarez FAlvarez F. Source Division of Gastroenterology-Nutrition, Hôpital Sainte-Justine, Montreal, Que. Abstract Treatment of chronic hepatitis B and C aims to achieve viral eradication. Decreasing the number of carriers subsequently reduces the transmission of the viruses. For an individual patient, therapy is aimed at preventing cirrhosis, liver failure and hepatocarcinoma. Among potential therapies, interferon alfa offers the best results. In one study involving the treatment of children from a region of intermediate endemicity, interferon alfa accelerated the clearance of hepatitis B virus (HBV) replication. In long-term follow-up, the study did not show a significant difference between patients who were treated and those who were not in the rate of disappearance of serum HBV-DNA, normalization of alanine aminotransferase (ALT) levels or seroconversion to antibodies to hepatitis B e antigen. The most important factors in predicting a rapid decrease inHBV replication were AIT levels more than twice normal, low levels of serum HBV-DNA (less than 100 pg/mL) and inflammatory activity on liver biopsy (chronic active hepatitis). A select group of children with HBV infection has thus been shown to benefit from interferon alfa therapy. Treatment should be administered in a dosage of 6 MU/m2 three times each week for 6 months. Chronic active hepatitis, develops in approximately 30% of children with a chronic hepatitis C virus (HCV) infection. Cirrhosis due to HCV appears to be a very rare complication among children. Results of interferon alfa treatment for children with HCV are scarce. A pilot study of 12 children treated with interferon alfa in a dosage of 3 MU/m2 three times each week for 6 months showed that ALT levels normalized in approximately 90% of the patients after 15 months of follow-up. All of the patients had a decrease in the histological activity of the disease. Factors predictive of a favourable response in adults were: low levels of gamma-glutamyl transferase, young age, female sex, short duration of disease, absence of cirrhosis and low histological activity of the disease. Controlled randomized studies are needed to determine the indications for interferon alfa therapy in children infected with HCV. Available data suggest that children may have a better response than adults.

82 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). 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.

83 Currently approved therapies  Standard interferon-α/Pegylated interferon-α— Interferon-α enhances the innate immune response by binding to the type 1 interferon receptor resulting in activation of the Jak-Stat pathway3 and up- regulation of multiple interferon-stimulated genes, which limit viral dissemination. With the addition of polyethylene glycol, pegylated interferon-α has a longer half-life than interferon-α. There are currently seven approved therapies for chronic hepatitis B infection in the USA

84  Nucleos(t)ide Analogues: These oral agents can be grouped by structure and function into three groups; the L- nucleosides, acyclic phosphonates, and other.  lamivudine, emtricitabine, and telbivudine.  adefovir dipivoxil (adefovir) and tenofovir disoproxil fumarate (TDF) Lamivudine is potent but is limited by the rapid development of resistance. The 100 mg dose of lamivudine results in a peak plasma concentration of 1.28 mcg/mL ± 0.56 mcg/mL that occurs between 0.5 and 2 hours after administration. The mean half-life is 5-7 hours.. Emtricitabine, given 200 mg orally, is not FDA approved for HBV, but it has been extensively used with tenofovir in HIV/HBV coinfected patients. It reaches peak plasma concentrations of 1.8 ± 0.7 mcg/mL at 1–2 hours and has a plasma half-life of 10 hours. It has slightly greater potency and efficacy than lamivudine but cannot be used as monotherapy due to high rates of resistance

85 Standard of Care: Pegylated Interferon and Ribavirin

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87 Before the development of cell culture, many viruses were propagated in embryonated chicken eggs. Today this method is most commonly used for growth of influenza virus. The excellent yield of virus from chicken eggs has led to their widespread use in research laboratories and for vaccine production.

88 Interferons (IFNs) were discovered about 50 years ago, as soluble factors produced by chicken cells of the chorio- allantoic membranes after contact with influenza virus, which interfered with subsequent viral infection. Type I and type III IFNs, also known as IFNs-alfa/beta and IFN lambda, can be produced by many cell types and primarily act as antiviral cytokines, although they also exhibit cytostatic activities and help to activate and shape the adaptive immune response. In contrast, type II IFN (or IFN- gamma is produced by cells of the immune system such as macrophages, T cells and natural killer cells. IFN gamma primarily acts as an immunomodulatory cytokine that notably contributes to T cell polarity and activates cellular immunity. INTERFERONI Early evidence pointed to a Dendritic Cells as being the main producer of IFN-α in response to stimulation with viruses.

89 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.

90 Figure 1. Infected and non-infected cells can produce IFN, using distinct pattern recognition receptors. Most cells express RIG-like helicases (RIG-I or MDA-5) that sense nucleic acids of viral origin in the cytoplasm and thus trigger IFN production by infected cells. Some cells, and particularly phagocytic cells, express TLRs that sense extracellular danger and pathogen- associated molecular patterns from the extracellular milieu. TLRs thus enable non-infected cells to sense viral components released by neighboring cells. TLR = Toll like receptors

91 IFN are subdivided into three distinct types. With together around 20 members the mammalian type I IFN (IFN-I) includes more than 10 IFN-α and usually a single IFN-β. the type II IFN, IFN-γ, which is produced predominantly by various T cell and NK cell populations. Type III IFN is comprised of three family members called IFN-λ1-3, or, synonymously, IL-29, IL-28A and IL-28B. Dominant IFN activities in the immune system are to protect cells from viral replication and to activate macrophages for enhanced effector function. However, the impact of IFN and their STATs on the immune system stretches far beyond these activities and includes the control of inflammation.

92 Although IFN is mostly known to be protective against RNA virus infection, it was also shown to protect the CNS against DNA viruses. Receptors of all IFN types belong to the class II of cytokine receptors and share the attribute of employing JAK-STAT signal transduction for nuclear signaling.

93 We recently elucidated the molecular mechanism of IFN-l-induced HBV inhibition, which we found to be common between IFN-l, IFN-a/-b, and IFN-g (Pagliaccetti and others 2010). All 3 IFN types inhibit HBV replication by preventing the assembly of viral RNAcontaining capsids in the cytoplasm (Wieland and others 2005).

94 PEG-IFN-α therapy for chronic HCV infection can cause neuropsychiatric disorders, including depression and suicidal behavior (Raison and others 2005; Asnis and De La Garza 2006), and direct action of the cytokine on cells of the central nervous system may play a role in these effects, which may also limit the therapeutic use of PEG-IFN-λ. Reazioni avverse da Interferoni

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

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99 Farmaci antivirali per virus a DNA

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101 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. Meccanismo di azione

102 Acyclovir and other nucleoside analogues are converted to active nucleoside triphosphates by viral and host cell kinases. These active nucleoside triphosphates compete with the corresponding endogenous nucleoside triphosphates and competitively inhibit viral DNA polymerase. Acyclovir and the nucleoside reverse transcriptase inhibitors (NRTIs) are incorporated into viral DNA and cause chain termination because they lack the 3'-hydroxyl group required to attach the next nucleoside. Ganciclovir and penciclovir do not cause chain termination.

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105 Virus dell’epatite C

106 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

107 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. Boceprevir Rizza, S.A., Talwani, R., Nehra, V., Temesgen, Z. Drugs Today 2011, 47(10): 743

108 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.

109 Hepatology.Hepatology Oct 18. doi: /hep [Epub ahead of print] Anemia during treatment with peginterferon alfa-2b/ribavirin and boceprevir: Analysis from the sprint-2 trial. Sulkowski MSSulkowski MS, Poordad F, Manns MP, Bronowicki JP, Reddy KR, Harrison SA, Afdhal NH, Sings HL, Pedicone LD, Koury KJ, Sniukiene V, Burroughs MH, Albrecht JK, Brass CA, Jacobson IM.Poordad FManns MPBronowicki JPReddy KRHarrison SAAfdhal NHSings HL Pedicone LDKoury KJSniukiene VBurroughs MHAlbrecht JKBrass CAJacobson IM Source Johns Hopkins University School of Medicine, Baltimore, MD, USA. Abstract Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously-untreated adults with chronic hepatitis C genotype-1. We evaluate the relationship of incident anemia with triple therapy patients received a 4-week lead-in of PegIFN/RBV followed by: 1) placebo plus PegIFN/RBV for 44 weeks (PR48); 2) BOC plus PegIFN/RBV using response- guided-therapy (BOC/RGT); and 3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, p< 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia.


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