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hiv and aids treatment

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  1. 1. RAMESH.KASARLA PharmD PB 2nd year. svcp 1
  2. 2. HIV • “Human immunodeficiency virus” is a lentivirus that causes the acquired immunodeficiency syndrome, a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers. • A unique type of virus (a retrovirus) • Invades the helper T cells (CD4 cells) in the body of the host (defense mechanism of a person) • Preventable, managable but not curable. 2
  3. 3. AIDS • “Acquired Immunodeficiency Syndrome” • HIV is the virus that causes AIDS • Disease limits the body’s ability to fight infection due to markedly reduced helper T cells. • Persons with positive HIV serology who have ever had a CD4 lymphocyte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14% are considered to have AIDS. 3
  4. 4. Natural History of HIV/AIDS • HIV was first clinically observed in 1981 in the United States • 1982 – First use of term “AIDS” • 1983 – Virus isolated and identified. • 1985 – HIV Ab testing available. • 1987 – First FDA approved drug (Zidovudine) NRTI. • 1988 – World Health Organization(WHO) Declared December 1st as “World AIDS Day” • 37.0 million people living with HIV/AIDS worldwide in spt-2015 • 1.7million people died of AIDS-related illnesses worldwide in 2015 • South Africa was the 1st country having 6,200,000 people living wth HIV. • India was the 3rd country having 2,400,000 people living with HIV 4
  5. 5. Structure and life cycle of HIV • HIV is a retrovirus – Contains two strands of (+)ssRNA • Contains reverse transcriptase and integrase. – Integrase helps in the insertion of HIV DNA into host DNA • Infects helper T cells and macrophages 5
  6. 6. • The outer membrane contains the proteins gp120 and gp41. Both are important to adsorption and penetration. • Gp120 binds to the transmembrane protein CD4 on the host cell and then is removed by conformational changes. • Gp41 then pulls the virus and host cell together allowing the membranes to fuse. • The capsid breaks down and the viral RNA and enzymes are release into the cell. • Reverse transcriptase converts the viral RNA into DNA. This DNA is known as proviral DNA • Integrase inserts the proviral DNA into the host’s DNA. Once the proviral DNA is part of the host’s DNA, it is known as the provirus and can remain dormant in the DNA 6
  7. 7. • When the provirus is transcribed, three main genes are transcribed: env, gag, and pol. • Three non-functional poly-proteins are made from these genes, one from the env gene, one from the gag gene, and the last one is from a combination of the gag and pol genes. • The first produces gp120 and gp41 which are placed onto the cell membrane. The other two poly-proteins move to the inner cell membrane and block out host membrane proteins. Budding occurs in this region of the membrane. • The gag-pol protein releases protease by autocatalysing the gag- pol protein. Protease then cleaves reverse transcriptase, integrase, and other proteins. • The capsid forms, with all viral RNA, essential enzymes, and proteins in it. The complete virus then leaves the host cell. 7
  8. 8. HIV LIFE CYCLE 8
  9. 9. Modes of HIV/AIDS Transmission Through Bodily Fluids  Blood products  Semen  Vaginal fluids  Breast Milk Intravenous Drug Abuse  Sharing Needles -Without sterilization Increases the chances of contracting HIV  Unsterilized blades 9
  10. 10. Mother-to-Baby Before Birth During Birth Through Sex Unprotected Intercourse Oral Anal 10
  11. 11. How HIV/AIDS not transmitted? 11
  12. 12. 12
  13. 13. Opportunistic Infections associated with AIDS CD4<500 • Bacterial infections • Tuberculosis (TB) • Herpes Simplex • Herpes Zoster • Vaginal candidiasis • Hairy leukoplakia • Kaposi’s sarcoma 13
  14. 14. 14
  15. 15. Testing Options for HIV Administration • Blood • Urine • Oral 15
  16. 16. Blood Detection Tests • Enzyme-Linked Immunosorbent Assay/Enzyme Immunoassay (ELISA/EIA) • Radio Immunoprecipitation Assay/Indirect Fluorescent Antibody Assay (RIP/IFA) • Polymerase Chain Reaction (PCR) • Western Blot Confirmatory test 16
  17. 17. Urine Testing • Urine Western Blot – As sensitive as testing blood – Safe way to screen for HIV – Can cause false positives in certain people at high risk for HIV 17
  18. 18. Oral Testing • Orasure – The only FDA approved HIV antibody. – As accurate as blood testing – Draws blood-derived fluids from the gum tissue. – NOT A SALIVA TEST! 18
  19. 19. 19
  20. 20. Classification of Antiretroviral medicines • NRTI (Nucleoside Reverse Transcriptase Inhibitors) • NtRTI (Nucleotide Reverse Transcriptase Inhibitors) • NNRTI ( Non-Nucleoside Reverse Transcriptase Inhibitors) • PI (Protease Inhibitors) • Other ARVs • Entry Inhibitors: Fusion Inhibitor: Enfuvirtide, Penitration blockrs: Maraviroc • Integrase inhibitors: Raltegravir, Elvitegravir • Maturation inhibitors: Beviramat 20
  21. 21. ARVs and the HIV Lifecycle 21
  22. 22. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors(NRTI’s) Agent Approved Dose frequency Zidovudine 3/87 300mg od Didanosine 10/91 250,400mg od Stavudine 6/94 15,20,30mg bd Lamivudine 11/95 100,150,300mg BD Abacavir 12/98 300mg BD Combivir 9/97 150/300mg BD Trizivir 11/00 150mg/300mg BD Tenofovir 10/01 150,200,250,300 mg OD Emtricitabine 7/03 200mg OD Epzicom 8/04 300mg/600mg OD Truvada 8/04 200mg/300mg OD 22
  23. 23. NRTI Mechanism of Action • NRTIs must first undergo intracellular phosphorylation to be active • NRTIs inhibit the viral reverse transcriptase enzyme – Enzyme responsible for transcribing viral RNA into double stranded DNA • NRTIs mimic other nucleosides and are incorporated into the DNA strand • They prevent the addition of the natural nucleosides into the DNA strand • This halts the production of new virions Clinical Pharmacology 2007. Gold Standard, Inc. 23
  24. 24. NRTI Adverse Effects Zidovudine • Bone marrow suppression (anemia/ neutropenia), Nausea, Nail discoloration Abacavir Hypersensitivity reaction: fever, rash, fatigue, malaise, nausea, vomiting, diarrhea, loss of appetite, pharyngitis Lamivudine Generally well-tolerated Emtricitabine Hyperpigmentation of palms and soles Stavudine • Peripheral neuropathy, Pancreatitis, Increased triglycerides Didanosine • Pancreatitis, Peripheral neuropathy, Diarrhea Tenofovir • GI upset, Flatulence, Nephrotoxicity NRTI Adverse Effects
  25. 25. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Agent Approved Dose frequency Nevirapine (Immediate Release) 6/96 200mg 400mg OD x14Days then OD Delavirdine 4/97 400mg TID Efavirenz 9/98 400mg BD Nevirapine (Extended Release) 6/11 400mg OD Rilpivirine 20-May-11 25mg OD Etravirine 18-Jan-08 200mg q12hrly 25
  26. 26. NNRTI Adverse Effects • Nevirapine: – Rash (7%), increased transaminase levels, hepatitis • Hepatotoxicty more common in women with pretreatment CD4+ cell counts > 250 cells/mm3 , men with CD4+ cell counts > 400 cells/mm3 and patients co-infected with hepatitis B or C • Monitor LFTs minimally at baseline, 2 weeks, monthly for the 1st 3 months in all patients • Efavirenz: – Rash (1.7%), increased transaminase levels, CNS side effects (e.g. vivid dreams, dizziness, drowsiness) NNRTI Adverse Effects 27
  27. 27. Protease Inhibitors (PIs) Agent Approve d Dose frequency Saquinavir -HGC 12/95 1000mg (500mg) BID Ritonavir 3/96 300mg,600mg BID Indinavir 3/96 800mg TID Nelfinavir 3/97 750mg 1250mg TID BID Saquinavir-SGC 11/97 1000mg BID Lopinavir/ritonavir 9/2000 400mg/100mg BID Atazanavir 6/03 400mg OD Fosamprenavir 10/03 1400mg BID Tipranavir 6/05 500mg BID Darunavir 6/06 600mg BID 28
  28. 28. PI Mechanism of Action • Protease enzyme is responsible for cleaving (cutting up) larger polyproteins into structural proteins and reverse transcriptase enzyme • Protease is needed to form a fully mature, functional virus that is able to replicate and produce more virus • Protease inhibitors prevent this enzyme from doing its job in the later steps of the viral life cycle Clinical Pharmacology 2007. Gold Standard, Inc. 29
  29. 29. PI Adverse Effects Amprenavir/fos-amprenavir GI intolerance, rash, oral paresthesias Atazanavir Hyperbilirubinemia Indinavir Nephrolithiasis, hyperbilirubinemia Lopinavir/ritonavir Nausea, diarrhea, pancreatitis Nelfinavir Diarrhea Ritonavir GI intolerance, paresthesias, asthenia, taste perversion, hepatitis Saquinavir GI intolerance Tipranavir GI intolerance, hepatitis, rash, intracranial hemorrhage Darunavir GI intolerance, rash
  30. 30. Fusion Inhibitor Fusion Inhibitor Mechanism of Action : • Inhibits entry of HIV into the CD4 cell • Enfuvirtide binds to glycoprotein gp41 (a protein on the viral membrane) • This binding prevents a change in the shape of the membrane protein and prevents fusion of the virus and the CD4 cell membrane Agent Approved Dose frequency Enfuvirtide (T-20, Fuzeon) 3/2003 90mg(IV) BID 31
  31. 31. Penetration blockers Mechanism of action: Maraviroc is a CCR5 inhibitor that binds to the host cell through CCR5 receptors. It is only active in patients who have virions that use CXCR5 for cell entry. Agent Approved Dose frequency Maraviroc 8/2007 300mg BID 32
  32. 32. HIV integrase strand transfer inhibitors(INSTI) Agent Approved Dose frequency Raltegravir 12--Oct-07 400mg BD Dolutegravir 13-August-13 500mg OD • Mechanism of action: Inhibits catalytic activity of integrase,an HIV encoded enzyme required for viral replication. 33
  33. 33. Initial Treatment: Preferred Components *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. • Efavirenz* OR • Atazanavir + ritonavir • Fosamprenavir + ritonavir (BID) • Lopinavir/ritonavir (BID) NNRTI Option PI Options  Tenofovir + emtricitabine** OR  Zidovudine + lamivudine** + NRTI Options 34
  34. 34. Initial Treatment: Alternative Components *Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts > 400 cells/mm3 **Atazanavir must be boosted with ritonavir if used in combination with tenofovir • Nevirapine* OR • Atazanavir** • Fosamprenavir • Fosamprenavir + ritonavir (QD) • Lopinavir/ritonavir (QD) NNRTI Option PI Options  Abacavir + lamivudine Or  Didanosine + (emtricitabine or lamivudine) NRTI Options + 35
  35. 35. Multi-class Combination Products Agent Approved Dose frequency Atripla: (efavirenz/ emtricitabine / tenofovir disoproxil fumarate ) 12-July-06 600mg/ 200mg / 300mg OD (E S) Complera : ( emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate ) 10-August-11 200mg/ 25mg / 300mg OD (W M) Stribild : ( elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate ) 27-August-12 150mg/ 150mg/ 200mg / 300mg OD (W M) 36
  36. 36. Drug interactions Agents Comment Stavudine + zidovudine Both thymidine analogs; antagonistic Stavudine + didanosine Increased risk of toxicities such as lactic acidosis and pancreatitis; may be considered when no other options available and potential benefits outweigh the risks. Emtricitabine + lamivudine Similar resistance profiles; no potential benefit Efavirenz in pregnancy Teratogenic Amprenavir oral solution Contraindications due to propylene glycol content Amprenavir + fosamprenavir Amprenavir is active component of both drugs Atazanavir + indinavir Potential for additive hyperbilirubinemia
  37. 37. Methods of control Preventive measures: • Refraining from unprotected Intercourse. • Refraining from intravenous drug use. • People who have HIV infection should not donate plasma, blood, organs for transplantation, tissue or cells. • All pregnant women must be counselled about HIV early in pregnancy and encouraged to undertake an HIV test as a routine part of standard antenatal care. • Those found to be HIV-positive take a course of ARV treatment, to reduce the risk of their infant being infected. 38
  38. 38. Methods of control (cont.) • Care must be taken in handling, using and disposing of needles or other sharp instruments. • WHO recommends immunization of asymptomatic HIVinfected children with the EPI vaccines; those who are symptomatic should not receive BCG vaccine. • Live Measles-Mumps-Rubella and polio vaccines are recommended for all HIV-infected children. • HIV testing and counselling is an important intervention for raising awareness of HIV status, promoting behavioural change and diagnosing HIV infection. 39
  39. 39. Conclusion • HIV/AIDS is a world epidemic. Although making new advances in combating this virus, there are many new infections every year. All should know what how it spreads and how to prevent it. Should take a HIV/AIDS test if involved in any risky behaviors. And also should tell others the importance of getting tested and prevention. • There is no cure for this virus, so there is no room for ignorance on this matter. 40
  40. 40. REFERENCE Pharmacotherapy, A Pathophysiologic approach by J.T.Dipiro 8 th edition,  R Chris Rathbun  Aberg, J. A., Kaplan, J. E., Libman, H., "Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America.  Book of MEDICINE 4th edition, Authors K George Mathew, Praveen Aggarwal, Anti Retroviral therapy.