Recent advances in the management of HIV infectionDr. Anil Kumar :Recent advances in the management of HIV infectionDr. Anil Kumar


Slide 2:Introduction Life cycle of HIV virus Clinical Stages of HIV/AIDS Anti Retro viral drugs Treatment guidelines PPTCT / PEP Newer investigational drugs HIV vaccines


Human Immunodeficiency virus :Human Immunodeficiency virus Retrovirus – lentiviridiae Chronic persistent infection Replication is continuous following infection RNA virus – 9300 base pairs 3 major open reading frames (GAG, POL, ENV ) Other regulatory proteins – TAT, NEF, VpF, REV – involved in viral production or combat host defences.


HIV data – India, 2006 :HIV data – India, 2006 Estimates approximately 0.36 percent, amounting to between 2 and 3.1 million people. More men are HIV positive than women. Nationally, the prevalence rate for adult females is 0.29 percent, while for males it is 0.43 percent.


Routes of Transmission of HIV :Routes of Transmission of HIV Sexual Contact: Male-to-male Male-to-female or vice versa Female-to-female Blood Exposure: Injecting drug use/needle sharing Occupational exposure Transfusion of blood products Transplanted organs Perinatal: Transmission from mother to baby Breast feeding


Incubation period :Incubation period 75% of HIV infected persons develop AIDS on an average of 10 years Incubation period. During this time, the virus is seriously damaging the infected person’s immune system.


Pathogenesis of HIV / AIDS Infected T-Cell :Pathogenesis of HIV / AIDS Infected T-Cell HIV Virus T-Cell HIV Infected T-Cell New HIV Virus


HIV binding & fusion :HIV binding & fusion


Life cycle of HIV :Life cycle of HIV


Window Period :Window Period This is the period of time after becoming infected when an HIV test is negative Usually, 90 percent of cases test positive within three months of exposure Diagnosis is by antigen detection (P24, HIV RNA assay)


HIV Infection and Antibody Response :HIV Infection and Antibody Response Infection Occurs AIDS Symptoms ---Initial Stage---- ---------------Intermediate or Latent Stage-------------- ---Illness Stage--- Flu-like Symptoms Or No Symptoms Symptom-free < ---- ----


HIV Detection Tests :HIV 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


Goals of Antiretroviral Therapy :Goals of Antiretroviral Therapy


ARV drugs : :ARV drugs : Block binding of HIV to target cell (fusion inhibitors) Block viral RNA cleavage and one that inhibits reverse transcriptase (reverse transcriptase inhibitors) Block the enzyme, integrase, which helps in the incorporation of the proviral DNA into the host cell chromosome (integrase inhibitors) Block the RNA to prevent viral protein production Block the enzyme protease (protease inhibitors) Inhibit the budding of virus from host cells (maturation inhibitors)


NRTIs – general considerations :NRTIs – general considerations Mechanism of action : - Phosphorylation - Lack 3’-OH group or have azido group : falsely incorporated into HIV genome, premature termination of chain elongation. Spectrum of activity – HIV 1&2, HBV, HTLV SE – mainly due to inhibition of mitochondrial DNA polymerase Gamma (anemia, granulocytopenia, myopathy, neuropathy, pancreatitis, lactic acidosis, hepatosteatosis)


NRTIs contd… :NRTIs contd… Absorption = 60-95%, least – ddI Food alters A of zalcitabine, ddI, AZT T1/2 ranges between 1-10hrs Eliminated primarily by renal route, except AZT & ABC (glucuronidation) Dosing – OD/BD, except zalcitabine (TID) Not substrates for CYP450 enzymes Not to be used as monotherapy – Resistance, more to thymidine analogues Mutations: M184V,L74V, D67N, K65R


Individual NRTIs :Individual NRTIs


Individual NRTIs :Individual NRTIs


Tenofovir :Tenofovir Prodrug-Tenofovir disoproxil fumarate, hydrolysed to tenofovir, Phosphorylated Analogue of adenosine-5’-monophosphate In adults, dose of 300mg OD A=25%, negligible protein binding, T1/2=17hrs, 70% excretion in urine SE: N,V,D, osteomalacia, pancreatitis, hepatomegaly HIV 1/2 , HBV DI: Increases conc of didanosine by inhibiting purine nucleotide polymerase, reduces conc of PIs (azatanavir)


NNRTIs- general considerations :NNRTIs- general considerations No need of phosphorylation Bind to hydrophobic pocket –P66 subunit of HIV 1 RT, conformational change, decrease the activity, non competative inhibition. Resistance: mutations K103N, Y181C – confers to entire group of NNRTI’S.


Individual NNRTIs :Individual NNRTIs


Protease inhibitors – general considerations :Protease inhibitors – general considerations Peptide like chemicals Prevent cleavage of HIV gag-pol polyproteins, preventing metamorphosis of the virion Bioavailability – variable, >96% protein binding, Half life-1.8-10hrs Substrates for CYP3A4, P gp Potent inhibitors also moderate inducers (ritonavir, nelfinavir, amprenavir)


Protease inhibitors….. :Protease inhibitors….. Metabolism : Hepatic oxidation Resistance development-intermediate btn NRTI & NNRTI, Cross resistance seen Mutations in codons 10, 46, 54, 82, 84 & 90. Produce favourable suppression of viremia, enhances CD4 level SE: Diarrhea, nausea, abdominal pain, lipodystrophy syndrome, Insulin resistance


Slide 32:Tipranavir: Sulfonamide moiety, Combined with ritonavir, contraindicated in hepatic insufficiency AE: N,V,D, abdominal pain, rash, hepatic enzyme elevation, intracranial hemorrhage Inhibits & induces CYP3A4 Darunavir: 600mg bd with ritonavir AE profile similar to tipranavir


Fusion inhibitors :Fusion inhibitors Enfuvirtide A synthetic 36-amino-acid peptide, N- terminal : acetylated, C-terminal: carboxamide binds to the gp 41- blocks the entry of HIV 1 into the cell T1/2 - 3.8hrs, Enzymatic hydrolysis SC injection, dose-90mg bd SE- local injection site reactions, hypersensitivity, eosinophilia Resistance : mutations in gp 41 codon


Maraviroc :Maraviroc Selective CCR5 antagonist Dose: 150mg bd T1/2 – 14-18hrs Substrate for CYP3A4, P gp FDA approved for CCR5 tropic HIV 1 virus SE- cough, joint pain, hepatotoxicity, risk of malignancy Resistance: mutations in gp 120 codon


Integrase inhibitors :Integrase inhibitors Raltegravir: FDA approval in October 2007 Targets integrase, integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. 400mg bd, T1/2 - 9hrs UGT-metabolism SE-diarrhea, CPK elevation


Treatment of HIV/AIDS :Treatment of HIV/AIDS Treatment of opportunistic infections ART Hematopoietic factors Prophylaxis of opportunistic infections


Opportunistic infections :Opportunistic infections CD4 <600/ul – Bacterial infection CD4 500-300 – TB, Herpes simplex, Zoster, Candidiasis, Hairy leukoplakia, Kaposi sarcoma CD4 <200: PCP, Toxoplasmosis, Cryptococcosis, Coccidiodomycosis, Cryptosporidiosis CD4 <50: Disseminated MAC, Histoplasmosis, CMV retinitis, CNS lymphoma


Initiating ART: Indications :Initiating ART: Indications Primary HIV infection: Not indicated Chronic HIV infection WHO stage IV disease irrespective of CD4 counts WHO stage I, II, III with CD4<200/%CD4<15 Evolving evidence for TLC<1200 as a predictor of CD4<200, however caution may be exercised while using it to offer therapeutic options PPTCT PEP


Guidelines contd….. :Guidelines contd…..


What to Expect in the First SixMonths of Therapy :What to Expect in the First SixMonths of Therapy CD4 recovery Early ARV toxicity Mortality on ART Immune reconstitution inflammatory syndrome - “occurrence or manifestations of new OIs or existing OIs within six weeks to six months after initiating ART; with an increase in CD4 count”. Treatment failure


ARV Toxicity :ARV Toxicity


Treatment failure :Treatment failure


PPTCT :PPTCT


ART Regimen :ART Regimen - Mother i. Antepartum: AZT + 3TC + NVP twice daily ii. Intrapartum: AZT + 3TC + NVP twice daily iii. Postpartum: AZT + 3TC + NVP twice daily - Infant i. AZT x 7 days* *If the mother receives less than 4 weeks of ART during pregnancy, 4 weeks of infant AZT is required


ARV Prophylaxis :ARV Prophylaxis - Mother i. Antepartum: AZT starting at 28 weeks of pregnancy or as soon as possible thereafter. ii. Intrapartum: Sd-NVP + AZT/3TC iii. Postpartum: AZT/3TC (7 days) - Infant i. Sd-NVP + AZT (7 days)


Post Exposure Prophylaxis (PEP) :Post Exposure Prophylaxis (PEP) Refers to comprehensive medical management to minimise the risk of infection among Health Care Personnel (HCP) following potential exposure to blood-borne pathogens (HIV, HBV, HCV).


Newer investigational drugs :Newer investigational drugs Elvucitabine Rilpivirine, IDX 899 GS 9350 Entry inhibitors: TNX 355, BMS 488043 CCR5 Antagonist: PRO 140, TBR 652 Intregase inhibitor: GSK 572 Maturation inhibitor: Bevirimat, Vivecon VpF inhibitors:


HIV Vaccines :HIV Vaccines


HIV vaccines :HIV vaccines


Slide 64:THANK YOU