Les Agents Antiretroviraux et Les Toxicites Associes avec Eux (French) Symposia presented in Milot, Haiti at Hôpital Sacré Coeur. CRUDEM’s Education Committee (a subcommittee of the Board of Directors) sponsors one-week medical symposia on specific medical topics, i.e. diabetes, infectious disease. The classes are held at Hôpital Sacré Coeur and doctors and nurses come from all over Haiti to attend.
Les Agents Antiretroviraux et Les Toxicites Associes avec Eux (French) Symposia
1. Les Agents Antiretroviraux et Les Toxicites Associes avec Eux Guesly Delva, M.D. Post Doc Infectious Disease Fellow Institute of Human Virology University of Maryland School of Medicine November 2011
2. TI Provirus Proteines ARN DNA ARN DNA DNA TI ARN ARN ADN ADN ADN L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux Entree/Fusion Transcriptase Inverse Integrase Protease
5. TI Provirus Proteines ARN DNA ARN DNA DNA TI Transcriptase Inverse ARN ARN ADN ADN ADN L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux
6. Stavudine Nom Commercial /Abbreviation Zerit, D4T Classe Analogue Nucleosidique (thymidine) Formulations & palatabilite Syrop: 1 mg/ml (gout: pas mal) Capsules: 15, 20, 30, 40 mg (petit, peut etre ouvert) Stock Syrop: DOIT ETRE REFRIGERE Caps: 15-30 C Dosage Enfant: 1 mg/kg up to 30 mg BD Adult: 30 mg BD Elimination Renale
7. Stavudine Interactions Zidovudine inhibit l’ activation de D4T – N’utiliser pas ensemble Toxicite augmentee avec ddI Tolerabilite, effets secondaires & toxicite Tolerabilite initiale: tres bonne Toxicite: moderee – acidose lactique, lipoatrophie, hyperlipidemie, resistance a l’insulin, hepatite, pancreatite, neuropathie (adults) Puissance Moderee Barriere Genetique a la resistance Moderee; hypersensitivite avec M184V
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9. Lamivudine Nom Commercial /Abbreviation Epivir, 3TC Classe Analogue Nucleosidique (cytosine) Formulations & palatabilite Syrop: 10 mg/ml (gout: super) Tablets: 150 mg (petit) Stock Syrop & tablet: Stable dans une temperature ambiante Dosage Enfant: 4 mg/kg BD Adult: 150 mg BD Elimination Renale
10. Lamivudine Interactions Aucun Tolerabilite, effets secondaires & toxicite Tres bien tolere Resurgence d’hepatite B possible lorsque ce medicament est stoppe Acidosis lactique?, hepatique? Puissance Moderee Barriere Genetique a la resistance Bas: la mutation M184V est facilement atteint est aboutisse a un haut niveau de resistance Mais cause aussi une augmentation de sensitivite au ZDV, D4T, et TDF et diminue le “ viral fitness”
11. Zidovudine Nom Commercial /Abbreviation Retrovir, ZDV, AZT Classe Analogue Nucleosidique (thymidine) Formulations & palatabilite Syrop: 10 mg/ml (gout: pas mal) Capsule: 100 mg (petit) Tablet: 300 mg (medium) Stock 15-25 C Dosage Enfant: 240 mg/m 2 BD Adult: 300 mg BD Elimination Glucuronidation hepatique and elimination de glucuronide dans l’urine
12. Zidovudine Interactions Zidovudine diminue l’activation D4T – N’utilisez pas ensemble Le rifampin reduit l’exposition de motie Tolerabilite, effets secondaires & toxicite Generalement bien tolere chez les enfants. Commun: anemie, neutropenie, trouble GI, fatigue, cephalee, ongles noiratre. Pas commun: myopathie, cardiomyopathie, hepatite, acidose lactique. Puissance Modere Barriere Genetique a la resistance Moderement haut Hypersensitive du virus avec la M184V
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14. Didanosine Nom Commercial /Abbreviation Videx DDI Classe Analogue Nucleosidique (adenosine) Formulations & palatabilite Suspension dans un antacide: 10 mg/ml (Gout d’antacide) Extended-release capsules (EC): 125 mg, 200 mg, 250 mg, 400 mg Stock Suspension: 4 C X 30 days Caps: temp ambiante Dosage Enfant: 120 mg/m 2 BD (pas pour EC) Adulte: < 60 kg 250 mg EC OD > 60 kg 400 mg EC OD Suspension doit etre pris a jeun Elimination Metabolisme extensive
15. Didanosine Interactions Incompatible avec la nourriture, tetracyclines, fluoroquinolones, ketoconazole, itraconazole, IDV, RTV, ATV, NFV, LPV/r, TDF. Niveau de ddI est augmente par le TDF & TDF/DDI reduit le CD4. Peut etre dose avec ZDV, D4T, EFV, NVP Tolerabilite, effets secondaires & toxicite Generalement bien tolere chez les enfants. Commun: pancreatite, neuropathie (principalement les adultes). Pas commun: Trouble GI toxicite hepatique, acidose lactique. Puissance Moderee Barriere Genetique a la resistance Moderee
16. Abacavir Nom Commercial /Abbreviation Ziagen, ABC Classe Analogue Nucleosidique (guanosine) Formulations & palatabilite Syrop: 20 mg/ml (gout: pas mal) Tablets: 300 mg Stock Temperature ambiante Dosage Enfant: 8 mg/kg BD Adulte: 300 mg BD Elimination Dehydrogenation, glucuronidation; metabolites excretes dans l’urine. Pas d’ajustment necassaire pour une faillite renale failure
17. Abacavir Interactions Inducteurs de glucuronidation peut reduire le niveau de ce molecule Tolerabilite, effets secondaires & toxicite Bien tol é r é . Nausee legere. Hypersensitivite: Commence quelques jours a 6 semaines apres le debut du traitement. Symptomes de fievre, rash, malaise ou hypotension, troubles GI, respiratoire. Progresse avec cahque dose. Peut etre fatale. Reaction severe va se produire si on recommence le molecule. Lie au genotype de HLA B5701. (~3% Europeens, ~1.6% Africains Sous-Sahariens) Puissance Mod érée - Haute (INTI le plus puissant) Barriere Genetique a la resistance Mod érée
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19. Temps Jusqu’a l’Apparition de Symptomes de la Reaction de Hypersensibilite d’ABC dans les Essais Cliniques (n=206) Nombre de Cas Jours depuis le 1er Dose d’ABC 89% des cas on ete observes moins de 6 semaines apres l’initiation d’ABC Temps moyen de commencement de symptomes 9 jours Data on file, GlaxoSmithKline.
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21. Tenofovir Nom Commercial /Abbreviation Viread, TDF Classe Analogue Nucleotidique Formulations & palatabilite Tablets: 300 mg Truvada: 300 mg TDF/200 mg FTC Stock Temperature ambiante Dosage Adulte: 300 mg OD (Enfant: ~210 mg/m2 OD) Elimination Renale
22. Tenofovir Interactions Minime Tolerabilite, effets secondaires & toxicite Très bien toléré Toxicité rénale (rare ) ? ?Perte osseuse minérale chez les enfants: observe chez les enfants prépubères, dans une étude, mais pas dans la deuxième étude Puissance Mod éré Barriere Genetique a la resistance Mod éré
26. Structures de Termination de Chaines N N O C H 3 O O O N 3 P O H O O DNA N N N N N H 2 O C H 3 C H 2 P O H O O DNA Tenofovir Zidovudine Analogue Nucleotidique Analogue Nucleosidique Phosphonate bond Phosphate bond Flexibility Bulky N 3 radical Minimal structure (reduced steric bulk)
27. Mechanisme de Function des INTI Incorporation Nucleotidique Incorporation de AZTMP dNTP N 3 AZT P N N 3 P N AZT dNTP P N P N
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29. Inhibition du Contient d’ADN Mitochondrial Apres 9 Jours d’Exposition aux INTI Cellules du Foie (HepG2 Cells) Cellules des Muscle squelettal Contient mtDNA (%) INTI ( µM) 0.1 1.0 10 100 1000 ddC ddI d4T ZDV ABC TDF 3TC Control Contient mtDNA (%) INTI ( µM) 0.1 1.0 10 100 1000 ddC ddI d4T ZDV 3TC TDF ABC Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723.
30. Etude 903: EFZ + 3TC + TDF ou d4T Patients (%) avec Quelques Toxicites Associees avec Les troubles de Fonctionnement Mitocondriaux + % Patients avec Quelques Toxicites TDF+3TC+EFV d4T+3TC+EFV Semaine 48 Semaine 96 Semaine 144 * * * * * * + Neurite/neuropathie Peripherique , lipodystrophie (definie par l’investigator), acidose lactique * p value < 0.001
32. ACTG 5142: Incidence de Lipoatrophy due aux INTI Stavudine Patients (%) 20% Zidovudine Tenofovir DF 16% 8% Semaine 48 Semaine 96 * P <0.001 versus tenofovir DF. † P =0.038 versus zidovudine. Haubrich R, et al. 14 th CROI. Los Angeles, 2007. Abstract 38. Lipoatrophy: > 20% loss of limb fat from baseline. 42%* † 27%* 9%
33. RT Provirus Proteins RNA DNA RNA DNA DNA RT Reverse transcriptase RNA RNA DNA DNA DNA L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux
34. Non-nucleoside drug binding site Nucleoside drug binding site pol active site RNase H active site thumb p51 Structure du Transcriptase Inverse du VIH
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36. Nevirapine Nom Commercial /Abbreviation Viramune, NVP Classe Inhibiteur Non-Nucl é osidique Transcriptase Inverse Formulations & palatabilite Suspension: 10 mg/ml (amere) Tabs: 200 mg (ligne division) Stock Temperature ambiante Dosage NVP doit etre donne OD pour les 2 premieres semaines (a moins qu’on change de l’EFV). Enfant: 120-200 mg/m 2 BD ( DOSAGE DOIT ETRE UTILISER POUR LES ENFANTS PLUS JEUNES - CONSULTEZ LE TABLEAU DE DOSASE) Adulte: 200 mg b.i.d.
37. Nevirapine Elimination Metabolisme hepatique P450 Interactions Rifampin diminue le NVP par 1/3- Utilisez l’EFV NVP diminue le ketoconazole par 2/3 NVP diminue le niveau de LPV- On doit augmenter le dosage LPV Tolerability, side effects & toxicity Commun: Rash. If legere, monitorez le LFTs, continuez le dosage. Si signes de Stevens-Johnson, discontinuez le molecule. Hepatites- peut etre severe, surtout avec CD4 eleve et chez les femmes. Monitors les LFTs chez les adultes. Le Risque chez les enfants n’est pas bien decrits. Puissance Haute Genetic barrier to resistance Tres bas – la resistance peut developper apres une dose unique sans autres ARV
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42. Efavirenz Nom Commercial /Abbreviation Sustiva, Stocrin, EFV Classe Inhibiteur Non-Nucl é osidique Transcriptase Inverse Formulations & palatabilite Caps: 50, 100, 200 mg; 600 mg tab Caps peuvent etre ouverts facilement, sans gout Liquide: 30 mg/ml ( LIQUIDE N’EST PAS BIEN ABSORBE- EVITEZ) Stock temperature ambiante Dosage Enfant: < 3 ans- evitez d; on doit utiliser un dosage relativement eleve - >3 ans: 15 mg/kg OD. Augmentez le dosage par 20% pour la forme liquide. Adulte: 600 mg OD Elimination Metabolisme hepatique P450
43. Efavirenz Interactions Diminue le niveau de LPV/r (augmneter le dosage), unboosted IPs “non-boostes”, autres medicaments Tolerabilite, effets secondaires & toxicite Commun: Effets SCN ephemere (le sommeil, drole de reve) s’ameliore apres quelque semaines/mois. Rash- if legere, continuez le dosage; si signes de Stevens-Johnson, discontinuez le molecule. Rare: transaminases augmentes. Teratogenicity possible (inconnu) Puissance Tres eleve Barriere Genetique a la resistance Tres bas. Resistance croisee leNVP et les autre INNTI.
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47. TI Provirus Proteines RNA DNA RNA DNA DNA TI Protease Viral RNA RNA DNA DNA DNA L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux
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49. Inhibiteurs de Protease sont des Inhibiteurs Competitifs du Protease Kempf D, et al. Abstract 129, First IAS Conference on HIV Pathogenesis and Treatment, July 8-11, 2001. 54 54 53 53 46 46 82 82 84 84 24 10 24 10 90 90 71 20 63 20 63 71
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52. Lopinavir/ritonavir Brand/Abbr. Aluvia, Kaletra, LPV/r Class Inhibiteur de Protease Formulations & palatability Solution: 80 mg/ml LPV + 20 mg/ml RTV (tres amere) Tabletss: 100 mg LPV/25 mg RTV 200 mg LPV/50 mg RTV Storage Stable 25 C X 2 mois. Maintener les capsules contre la l’humidite. Tablets sont stable. Dosage Prenez bouchons avec de la nourriture; capsules avec ou sans nourritures Enfant> 1 mois: 230 - 300mg/m2 LPV BD (dosage plus élevé pour les jeunes enfants) Adulte: 400 mg LPV BD
53. Lopinavir/ritonavir Elimination Hepatic P450 metabolism Interactions Inhibiteur très puissant du cytochrome P450-enzymes affecte l'élimination de plusieurs médicaments. La rifampicine diminue LPV à ¼. Double dose peut travailler dans les adultes avec la rifampicine, mais pas avec les enfants. Augmenter le dosage 1 / 3 avec la NVP ou EFV. Tolerability, side effects & toxicity Commune: Nausées et vomissements diarrhée>; altération du goût. Effets de classe y compris les augmentations du cholestérol; résistance à l'insuline Potency Extrêmement élevé Genetic barrier to resistance Extrêmement élevé. Nécessite mutations 5-10
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55. TI Provirus Proteines RNA DNA RNA DNA DNA TI RNA RNA DNA DNA DNA Entree L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux
56. SAQUINAVIR MESYLATE M.W. 767 ZIDOVUDINE M.W. 267 O N H 2 N H O O N H 2 N H O N H 2 O O H O O N H 2 O T-20 M.W. 4,492 O N H N H O N H 2 N H N H O N H O N H N H O O O H N H O N H O O O H N H O N H 2 N H O N H N H O N H O O H N H O N H O N H O N H O O N H 2 N H O N H O O O H N H O O O H N H O N H 2 N H O O N H 2 N H O O N H 2 N H O O H N H O O H N H O O H N H O N H O N H O N H N N H O O H N H O N H O N H O O O H N H O O O H N H O O H N H O
59. Tropisme: Usage de Co-recepteur par le VIH-1 AAC 2005, 16:339-354 & AIDS 2006, 20: 1359-1367
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62. TI Provirus Proteines ARN DNA ARN DNA DNA TI ARN ARN ADN ADN ADN L’Evolution de Vie du VIH-1 Et Les Cibles Majeurs Agents Antiretroviraux Integrase
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65. Categorie Example Description A Aucun (Etude Controlles…Pas de risques aux humains) B ddI, TDF, FTC, NFV (Etudes sur les animaux…no DRV, RTV, SQV, ATV anomalies mais pas d’etudes Maraviroc, Etravirine humains) C ZDV, ddC, d4T, 3TC (Etudes sur les animaux ont fetal ABC, NVP, DLV, revele des anormalities fetales IDV, APV, fAPV, LPV/r mais pas d’etudes humains , a TPV, Raltegravir utiliser seulement si benefice> risques) D EFV Risques d’anomalies fetale but Hydroxyurea benefice >risque Risques Pendant La Grossesse
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Notas del editor
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
This slide demonstrates the 2 unique features of tenofovir: 1) the unique phosphonate bond, which makes it less susceptible to excision and 2) the flexible and minimal structure, which reduces the potential for steric hinderance and increases flexibility.
Slide #27: Inhibition of Mitochondrial DNA Content After 9 Days of NRTI Exposure Birkus and colleagues demonstrated that tenofovir DF (3 to 300 µM) for up to 3 weeks produced no significant changes in mtDNA levels in human hepatoblastoma cells and skeletal muscle cells. 1 Of the NRTIs tested, the potencies of mtDNA inhibition, from highest to lowest were zalcitabine > didanosine > stavudine > zidovudine > lamivudine = abacavir = tenofovir DF in the cell-type models. Reference Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother . 2002;46:716-723.
Again, statistically significant differences between the two arms of the study in toxicities associated with mitochondrial dysfunction were observed through Week 48, Week 96, and Week 144.
Top left and right 53 year old man; HIV-infected since at least 1987 Received AZT + 3TC Later added IDV; 19 months of PI therapy Bottom left 46 year old man; HIV-infected since 1989 Received AZT in 1990 Added ddC in 1991 Added SQV in 1994 Noticed neck thickness in 1995 Bottom right 34 year old man; HIV-infected since 1993 Received AZT in 1993 Added 3TC and IDV in April and June 1996 Buffalo hump observed in December 1996
Slide #38: ACTG 5142: Incidence of Lipoatrophy by NRTI The incidence of lipoatrophy at week 96 was significantly higher in patients who received either stavudine or zidovudine compared with tenofovir DF (42% and 27% versus 9%, P <0.001 and P =0.038). 1 Reference Haubrich RH, Riddler S, DiRienzo G, et al. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. In: Program and abstracts of the 14 th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 38.
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
Shown here is the crystal structure of HIV-1 reverse transcriptase which folds like human right hand with subdomains fingers, palm, thumb, connection and Rnase H domain. The nucleic-acid substrate binds at a cleft extending from DNA polymerase site to the Rnase H site over palm and connection sub-domain. The non-nucleoside inhibitors bind to HIV-1 RT at a site near to but distinct from the dNTP substrate binding site. The palm subdomain is the RT catalytic active site. Here reside the three highly conserved and essential carboxylate residues as well as a handful of residues involved in NRTI resistance and NNRTI resistance however; Nnrti resistance will not be discussed today and we’ll focus on NRTI resistance.
Suppressed VL is a protective factor and a switch to NVP from EFV in is feasible and safe (e g TB treatment) without need for lead-in phase. Category B Negative rodent teratogenicity assays Single Dose Nevirapine: Single dose of 200 mg to the mother at delivery and one infant dose of 2 m/kg shown to be effective in reducing transmission to 7-12% and 3-7% with addition of AZT from week 28-32. However, resistance mutations are detected in 60-80% of patients after single dose of NVP and failure of a NVP containing regimen has been demonstrated in mothers and infants (NEJM 2010 363: 1499 and 1510).
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
Eleven changes in HIV protease were found by statistical methods to be significantly associated with a degree of change in phenotypic susceptibility to LPV. The impact of acquiring one of these mutations is not necessarily equal and some are found only in association with many other mutations. pts were NNRTI experienced (contrast to M98-957, the study that established the LPV genotypic breakpoint) The mutations are depicted in the context of the 3D structure of HIV protease. The protease is a dimer, so for every one mutation there are two possible sites at which it can occur. Most of these are secondary mutations, occurring outside the active site of HIV protease. The 82 and 84 mutations, which are found within the active site, and the 90 mutation are considered primary mutations for the PI class. Consistent with the fact that these mutations were found in patients failing therapy with other PIs, all these mutations are also selected by other PIs besides LPV. The mutation at position 53 is the least common, and it appears in conjunction with a median of seven other mutations, in viruses already very phenotypically-resistant to LPV. 80
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
This slide best shows a typical ISR on a patient’s abdomen, and is primarily a tactile reaction rather than a visual one. By running your hand over this this area of erythema, one would appreciate a slightly raised area of induration. Patients typically complain of itching and often liken these reactions to insect bites.
As shown in the pictorial, the R5 HIV exclusively utilizes the CCR5 co-receptor to infect the CD4 + T cell, and X4 HIV exclusively utilizes the CXCR4 co-receptor. D/M virus can enter the cell via either of the 2 co-receptors. 1-3 References 1. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother . 2005;16:339-354. 2. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS . 2006;20:1359-1367. 3. Berger EA, Doms RW, Feny ö E-M, et al. A new classification for HIV-1. Nature . 1998;391:240.
SELZENTRY is a selective and slowly reversible small-molecule antagonist of the interaction between the human chemokine CCR5 co-receptor and HIV-1 gp120. By blocking this interaction, SELZENTRY prevents CCR5-tropic HIV-1 entry into cells. Maraviroc is a powder, white to pale colored, with a molecular weight of 513.67. It is highly soluble across the physiologic pH range (1.0 to 7.5). Reference SELZENTRY [prescribing information]. New York, NY: Pfizer Inc; 2007.
This is the HIV cycle. I am also sure you are all familiar with it. The virus fuses with the cell membrane, releasing the viral genetic material and some needed enzymes. The process of transcription is initiated, that let to the final formation of double stranded DNA. This DS DNA enters the nucleolus of the cell, where is integrated with the host cell DNA. Eventually this is going to let to the formation of RNA, that will be transcribed into viral proteins, These viral proteins are assemble into a viable virion by the protease, that buds out of the cell, propagating the infection.
Raltegravir (MK-0518) is a novel integrase strand transfer inhibitor recently approved by the FDA. Raltegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy and HIV-1 strains resistant to multiple antiretroviral agents. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. Integrase strand transfer inhibitors are unique in that they bind to the active site of integrase and selectively inhibit the strand transfer step of HIV-1 replication. 1 By inhibiting integration, raltegravir has been shown to enhance the formation of dead-end 2-LTR circular DNA products. 2 References 1. Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDs. 2006;20:489–501. 2. Miller M, Witmer M, Stillmock K, et al. Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor. XVI Int AIDS Conf. 2006; August 13 –18. Abstract ThAa0302. http://www.aegis.com/conferences/iac/2006/ThAa0302.html. Accessed July 20, 2007. Miller, Results: para 2 Lataillade, pg 493, col 2, para 2 PI, pg 10, para 1 PI, pg 10, para 2 PI, pg 1 para 1